Molecules

15 pages, 512 KiB

Open AccessArticle

Antitrypanosomal and Antileishmanial Activities of Tacca leontopetaloides Tubers and Zanthoxylum zanthoxyloides Stem Bark

by Elizabeth O. Agbo^1,2, John V. Anyam^1,3, Cyprian T. Agber^1,2, Christie A. Adah^1,2, Christopher Agbo⁴, Augustina O. Ijeomah⁵, Terrumun A. Tor-Anyiin⁵, Hamed E. Alkhalaf⁶

, Aditya Sarode⁷

, Jamal I. Asseri⁶, Alexander I. Gray⁸, John O. Igoli^1,5,*

and Harry P. De Koning^6,*

¹ Phytochemistry Research Group, Department of Chemistry, Joseph Sarwuan Tarka University, Makurdi PMB 2373, Benue State, Nigeria

² Department of Chemistry, Benue State University, Makurdi PMB 102119, Benue State, Nigeria

³ Centre for African Medicinal Plant Research, North-Eastern University, Gombe 771104, Gombe State, Nigeria

⁴ Department of Microbiology, Joseph Sarwuan Tarka University, Makurdi PMB 2373, Benue State, Nigeria

⁵ Department of Chemistry, Joseph Sarwuan Tarka University, Makurdi PMB 2373, Benue State, Nigeria

⁶ School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK

⁷ Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G4 0RE, UK

⁸ Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK

Molecules 2025, 30(11), 2468; https://doi.org/10.3390/molecules30112468 - 5 Jun 2025

Viewed by 495

Abstract

The phytochemical screening of extracts of Tacca leontopetaloides tubers has afforded the isolation of two novel chalcones, tarkalynins A and B, along with taccalonolide A and its 12-propanoate. The screening of Zanthoxylum zanthoxyloides stem bark yielded taraxerol acetate, dihydrochelerythrin and fagaramide. These compounds [...] Read more.

The phytochemical screening of extracts of Tacca leontopetaloides tubers has afforded the isolation of two novel chalcones, tarkalynins A and B, along with taccalonolide A and its 12-propanoate. The screening of Zanthoxylum zanthoxyloides stem bark yielded taraxerol acetate, dihydrochelerythrin and fagaramide. These compounds were obtained through column and thin-layer chromatography and identified using NMR and LC-HRMS. The compounds were tested against Trypanosoma brucei brucei s427 and its multi-drug-resistant clone B48, against Trypanosoma evansi, Trypanosoma equiperdum and Trypanosoma congolense, and against Leishmania mexicana. Cytotoxicity was tested against the human HEK293 cell line. The highest activities were observed with dihydrochelerythrin and fagaramide against T. b. brucei s427 and B48, T. evansi, and L. mexicana, with EC₅₀ values of 1.37, 2.559, 1.09, and 5.44 µM and 17.8, 10.9, 10.9, and 13.3 µM, respectively. In addition, tarkalynin A and taraxerol acetate displayed promising activity against T. equiperdum (EC₅₀ = 21.4 and 21.3 µM, respectively). None of these compounds showed significant cross-resistance with existing trypanocides (RF ≈ 1; p > 0.05). The compounds displayed low toxicity to human cells, with most exhibiting no growth inhibition at concentrations of 100, or even 300 µM. This report provides further evidence of the potential use of natural products for combating parasitic diseases. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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23 pages, 2217 KiB

Open AccessFeature PaperArticle

Antiprotozoal Aminosteroids from Pachysandra terminalis

by Lizanne Schäfer¹, Monica Cal^2,3, Marcel Kaiser^2,3

, Pascal Mäser^2,3

and Thomas J. Schmidt^1,*

¹ University of Münster, Institute of Pharmaceutical Biology and Phytochemistry (IPBP), PharmaCampus Corrensstraße 48, D-48149 Münster, Germany

² Swiss Tropical and Public Health Institute (Swiss TPH), Kreuzstrasse 2, CH-4123 Allschwil, Switzerland

³ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

Molecules 2025, 30(5), 1093; https://doi.org/10.3390/molecules30051093 - 27 Feb 2025

Viewed by 858

Abstract

Trypanosoma brucei rhodesiense (Tbr) and Plasmodium falciparum (Pf) are protozoan parasites that cause severe diseases, namely, Human African Trypanosomiasis (HAT) and Malaria. Due to limited treatment options, there is an urgent need for new antiprotozoal drugs. Pachysandra terminalis ( [...] Read more.

Trypanosoma brucei rhodesiense (Tbr) and Plasmodium falciparum (Pf) are protozoan parasites that cause severe diseases, namely, Human African Trypanosomiasis (HAT) and Malaria. Due to limited treatment options, there is an urgent need for new antiprotozoal drugs. Pachysandra terminalis (P. terminalis), a plant belonging to the family Buxaceae, is known as a rich source of aminosteroid alkaloids, and a previous study of our working group already showed that the alkaloid-enriched fraction of P. terminalis aerial parts showed promising activity against protozoan parasites. In the present study, the alkaloid-enriched fraction obtained from a 75% ethanol extract of aerial parts was separated to isolate a chemically diverse array of Pachysandra alkaloids for assessment of their antiprotozoal activity and later structure–activity studies. This work yielded a new megastigmane alkaloid (1), 7 new aminosteroids (2, 7, 16, 17, 18, 19, 20), along with 10 known aminosteroids (3–5, 8, 10–15) and 2 artifacts (6, 9) that were formed during the isolation process. The structures were elucidated by UHPLC/+ESI-QqTOF-MS/MS, as well as extensive 1- and 2D-NMR measurements. The extract and its fractions, as well as the isolated compounds, were tested in vitro against Tbr and Pf, as well as cytotoxicity against mammalian cells (L6 cell line). The activity (IC₅₀ values) of the isolated alkaloids ranged between 0.11 and 26 µM (Tbr) and 0.39 and 80 µM (Pf). 3α,4α-diapachysanaximine A (7) showed the highest activity against Tbr (IC₅₀ = 0.11 µM) with a selectivity index (SI) of 133 and was also quite active against Pf with IC₅₀ = 0.63 µM (SI = 23). This compound is, therefore, a promising new antiprotozoal target for further investigations. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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14 pages, 1240 KiB

Open AccessArticle

Bioactive Compounds with Leishmanicidal Potential from Helianthus tuberosus and Vernonanthura squamulosa

by Rachel Nápoles Rodríguez¹

, María Laura Arreguez², Aldana M. Corlatti^1,3

, Hernán G. Bach⁴, César A. N. Catalán⁵

, Laura C. Laurella^1,3, Paola A. Barroso^2,*

and Valeria P. Sülsen^1,3,*

¹ CONICET-Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Autonomous City of Buenos Aires C1113AAD, Argentina

² CONICET-Universidad Nacional de Salta, Instituto de Patología Experimental (IPE), Salta A4400, Argentina

³ Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Farmacognosia, Autonomous City of Buenos Aires C1113AAD, Argentina

⁴ Instituto Nacional de Tecnología Agropecuaria, Buenos Aires B1686, Argentina

⁵ Instituto de Química Orgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Miguel de Tucumán, Tucumán T4000INI, Argentina

Molecules 2025, 30(5), 1039; https://doi.org/10.3390/molecules30051039 - 24 Feb 2025

Viewed by 716

Abstract

Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. An estimated 700,000 to 1 million new cases occur annually. Current therapies are limited by high toxicity, cost, prolonged treatment period, and rising resistance in endemic regions. The [...] Read more.

Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. An estimated 700,000 to 1 million new cases occur annually. Current therapies are limited by high toxicity, cost, prolonged treatment period, and rising resistance in endemic regions. The Asteraceae family has emerged as a promising source of bioactive compounds with proven leishmanicidal activity. In this study, the assessment of the antileishmanial activity of Helianthus tuberosus and Vernonanthura squamulosa extracts, the isolation of the sesquiterpene lactones heliangin and glaucolide A, respectively, and the evaluation of the activity of the compounds were conducted. Dichloromethane extracts of H. tuberosus and V. squamulosa were active on Leishmania amazonensis promastigotes, inhibiting the replication of the parasites in 97.2 ± 3.1% and 89.1 ± 1.1%, respectively, at 100 μg/mL. Heliangin was active against promastigotes of L. amazonensis (IC₅₀ = 9.3 μM) and intracellular amastigotes (IC₅₀ = 0.8 μM), while glaucolide A exhibited moderate activity against promastigotes (IC₅₀ = 46.7 μM) and did not show activity against intracellular amastigotes. Based on these results, heliangin was further evaluated in an animal model of cutaneous leishmaniasis using BALB/c mice infected with L. amazonensis. Heliangin (8 mg/Kg), when administered in combination with Glucantime, significantly reduced lesion progression and parasite load compared to the vehicle-treated group (p < 0.001). These findings show that heliangin is a potential candidate for leishmaniasis treatment, especially in combination with therapeutic drugs. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 1201 KiB

Open AccessArticle

In Vitro and In Vivo Evaluation of the Antischistosomal Activity of Polygodial and 9-Deoxymuzigadial Isolated from Drimys brasiliensis Branches

by Eric Umehara¹, Rayssa A. Cajas², Gabriel B. Conceição², Guilherme M. Antar³

, Adriano D. Andricopulo^4,5

, Josué de Moraes^2,5,6,*

and João Henrique G. Lago^1,5,*

¹ Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André 09280-560, SP, Brazil

² Núcleo de Pesquisas em Doenças Negligenciadas, Universidade Guarulhos, Guarulhos 07023-070, SP, Brazil

³ Departamento de Ciências Agrárias e Biológicas, Universidade Federal do Espírito Santo, São Mateus 29932-540, ES, Brazil

⁴ Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos 13563-120, SP, Brazil

⁵ Centro de Pesquisa e Inovação Especial em Ciências da Descoberta de Medicamentos (CEPIMED), Universidade de São Paulo, São Carlos 13563-120, SP, Brazil

⁶ Núcleo de Pesquisas em Doenças Negligenciadas, Instituto Científico e Tecnológico, Universidade Brasil, São Paulo 08230-030, SP, Brazil

Molecules 2025, 30(2), 267; https://doi.org/10.3390/molecules30020267 - 11 Jan 2025

Cited by 1 | Viewed by 1077

Abstract

In the present study, the hexane extract from branches of Drimys brasiliensis (Winteraceae) displayed potent activity against Schistosoma mansoni parasites (100% mortality of the worms at 200 μg/mL). Bioactivity-guided fractionation afforded, in addition to the previously reported bioactive sesquiterpene 3,6-epidioxy-bisabola-1,10-diene, two chemically related [...] Read more.

In the present study, the hexane extract from branches of Drimys brasiliensis (Winteraceae) displayed potent activity against Schistosoma mansoni parasites (100% mortality of the worms at 200 μg/mL). Bioactivity-guided fractionation afforded, in addition to the previously reported bioactive sesquiterpene 3,6-epidioxy-bisabola-1,10-diene, two chemically related drimane sesquiterpenes—polygodial (1) and 9-deoxymuzigadial (2). The anti-S. mansoni effects for compounds 1 and 2 were determined in vitro, with compound 1 demonstrating significant potency (EC₅₀ value of 10 μM for both male and female worms), while 2 was inactive. Cytotoxicity assays against Vero cells revealed no toxicity for either compound (CC₅₀ > 200 μM). Additionally, an in silico analysis was conducted using the SwissADME platform for 1, revealing that this natural sesquiterpene exhibited adherence to several ADME parameters and no PAINS violations. Finally, in vivo studies with S. mansoni-infected mice treated with compound 1 demonstrated a 44.0% reduction in worm burden, accompanied by decreases in egg production of 71.8% in feces and 69.5% in intestines. These findings highlight the potential of polygodial (1) as a promising prototype for schistosomiasis treatment. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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30 pages, 3254 KiB

Open AccessArticle

Towards Novel Antiplasmodial Agents—Design, Synthesis and Antimalarial Activity of Second-Generation β-Carboline/Chloroquine Hybrids

by Ana Penava¹, Marina Marinović¹

, Lais Pessanha de Carvalho², Jana Held^2,3

, Ivo Piantanida⁴

, Dijana Pavlović Saftić⁴

, Zrinka Rajić^1,* and Ivana Perković^1,*

¹ Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, 10000 Zagreb, Croatia

² Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen, Germany

³ Partner Site Tübingen, German Center for Infection Research (DZIF), 72074 Tübingen, Germany

⁴ Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia

Molecules 2024, 29(24), 5991; https://doi.org/10.3390/molecules29245991 - 19 Dec 2024

Viewed by 1249

Abstract

As the resistance of Plasmodium to the existing antimalarials increases, there is a crucial need to expand the antimalarial drug pipeline. We recently identified potent antimalarial compounds, namely harmiquins, hybrids derived from the β-carboline alkaloid harmine and 4-amino-7-chloroquinoline, a key structural motif of [...] Read more.

As the resistance of Plasmodium to the existing antimalarials increases, there is a crucial need to expand the antimalarial drug pipeline. We recently identified potent antimalarial compounds, namely harmiquins, hybrids derived from the β-carboline alkaloid harmine and 4-amino-7-chloroquinoline, a key structural motif of chloroquine (CQ). To further explore the structure−activity relationship, we synthesised 13 novel hybrid compounds at the position N-9 of the β-carboline ring and evaluated their efficacy in vitro against Plasmodium falciparum 3D7 and Dd2 strains (CQ sensitive and multi-drug resistant, respectively). All compounds exhibit persistent antimalarial activity against both strains of P. falciparum. The most interesting derivatives had low nanomolar activity against both strains (IC₅₀ (33) = 4.7 ± 1.3 nM against Pf3D7 and 6.5 ± 2.5 nM against PfDd2; IC₅₀ (37) = 4.6 ± 0.6 nM against 3D7 and 10.5 ± 0.4 nM against Dd2). Resistance indices (RIs) ranged from 0.9 to 5.3 compared to CQ (RI = 14.4), highlighting their superior consistency in activity against both strains. The cytotoxicity screening performed on HepG2 revealed over 3 orders of magnitude higher IC₅₀ for most of the compounds, with SIs from 711.0 to 8081.8. Spectroscopic studies explored the affinities of newly synthesised compounds for DNA, RNA, and HSA. Both tested hybrids, 34 and 39, were intrinsically fluorescent in an aqueous medium, characterised by remarkable Stokes shifts of emission maxima (Δλ = +103 and +93 nm for 34 and 39, respectively). Fluorimetric experiments revealed that compound 34, with its shorter and more flexible linker, exhibited at least an order of magnitude higher affinity toward ds-DNAs versus ds-RNA and two orders of magnitude higher affinity toward GC-DNAs compared to 39. The behaviour of the investigated compounds upon binding to HSA is very similar, showing a strong hypsochromic shift of the emission maximum (almost Δλ = −70 nm) and demonstrating their effectiveness as fluorimetric probes for distinguishing between DNA/RNA and proteins. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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17 pages, 2404 KiB

Open AccessArticle

Plant Extracts and Phytochemicals from the Asteraceae Family with Antiviral Properties

by Jimena Borgo^1,2,†

, Mariel S. Wagner^3,†

, Laura C. Laurella^1,2

, Orlando G. Elso^2,4

, Mariana G. Selener², María Clavin², Hernán Bach⁵, César A. N. Catalán⁶

, Augusto E. Bivona^7,8

, Claudia S. Sepúlveda^9,*,‡

and Valeria P. Sülsen^1,2,*,‡

¹ Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, Piso 2, Buenos Aires C1113AAD, Argentina

² Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Piso 2, Buenos Aires C1113AAD, Argentina

³ Laboratorio de Estrategias Antivirales, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Int. Güiraldes 2160, Piso 4, Buenos Aires C1428EGA, Argentina

⁴ Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), Facultad de Ciencias Exactas y Naturales, CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Piso 3, Buenos Aires C1428EGA, Argentina

⁵ Instituto Nacional de Tecnología Agropecuaria (INTA) Gobernador Guillermo Udaondo 1695 Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires, EEA AMBA Udaondo, Villa Udaondo B1713AAW, Buenos Aires Province, Argentina

⁶ Instituto de Química Orgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, San Miguel de Tucumán T4000INI, Tucumán Province, Argentina

⁷ Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni (IDEHU), CONICET-Universidad de Buenos Aires, Junín 956, Piso 4, Buenos Aires C1113AAD, Argentina

⁸ Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), CONICET-Universidad de Buenos Aires, Paraguay 2155, Piso 13, Buenos Aires C1121ABG, Argentina

⁹ Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, Int. Güiraldes 2160, Piso 4, Buenos Aires C1428EGA, Argentina

^† These authors contributed equally to this work.

^‡ The work was co-directed by both authors.

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Molecules 2024, 29(4), 814; https://doi.org/10.3390/molecules29040814 - 9 Feb 2024

Cited by 4 | Viewed by 3938

Abstract

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on [...] Read more.

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on a series of dichloromethane and methanolic extracts prepared from six Asteraceae species, including Acmella bellidioides, Campuloclinium macrocephalum, Grindelia pulchella, Grindelia chiloensis, Helenium radiatum, and Viguiera tuberosa, along with pure phytochemicals isolated from Asteraceae: mikanolide (1), eupatoriopicrin (2), eupahakonenin B (3), minimolide (4), estafietin (5), 2-oxo-8-deoxyligustrin (6), santhemoidin C (7), euparin (8), jaceidin (9), nepetin (10), jaceosidin (11), eryodictiol (12), eupatorin (13), and 5-demethylsinensetin (14). Results showed that the dichloromethane extracts of C. macrocephalum and H. radiatum and the methanolic extracts prepared from C. macrocephalum and G. pulchella were highly active and selective against DENV-2, affording EC₅₀ values of 0.11, 0.15, 1.80, and 3.85 µg/mL, respectively, and SIs of 171.0, 18.8, >17.36, and 64.9, respectively. From the pool of phytochemicals tested, compounds 6, 7, and 8 stand out as the most active (EC₅₀ = 3.7, 3.1, and 6.8 µM, respectively; SI = 5.9, 6.7, and >73.4, respectively). These results demonstrate that Asteraceae species and their chemical constituents represent valuable sources of new antiviral molecules. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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17 pages, 1503 KiB

Open AccessArticle

In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase

by Katharina Possart¹, Fabian C. Herrmann¹, Joachim Jose²

and Thomas J. Schmidt^1,*

¹ University of Muenster, Institute for Pharmaceutical Biology and Phytochemistry (IPBP), PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany

² University of Muenster, Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany

Molecules 2023, 28(22), 7526; https://doi.org/10.3390/molecules28227526 - 10 Nov 2023

Cited by 7 | Viewed by 2505

Abstract

The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses’ [...] Read more.

The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses’ health threats. The parasites’ frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the Tb enzymes (0.2 μM < IC₅₀ < 85.1 μM) and ten against the respective Lm enzymes (0.6 μM < IC₅₀ < 84.5 μM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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16 pages, 312 KiB

Open AccessArticle

In Vitro Effect on Plasmodium falciparum and In Vivo Effect on Plasmodium berghei of Annomaal, an Oily Fraction Obtained from the Seeds of Annona squamosa

by Sampada S. Sawant^1,2, Satish Y. Gabhe¹ and Kamalinder K. Singh^1,3,4,*

¹ C.U. Shah College of Pharmacy, SNDT Women’s University, Santacruz (West), Mumbai 400049, India

² Cipla Limited, Mumbai 400013, India

³ School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK

⁴ Biomedical Evidence Based Transdisciplinary Health Research Institute, University of Central Lancashire, Preston PR1 2HE, UK

Molecules 2023, 28(14), 5472; https://doi.org/10.3390/molecules28145472 - 17 Jul 2023

Cited by 5 | Viewed by 2697

Abstract

Malaria remains a life-threatening health problem and is responsible for the high rates of mortality and morbidity in the tropical and subtropical regions of the world. The increasing threat of drug resistance to available artemisinin-based therapy warrants an urgent need to develop new [...] Read more.

Malaria remains a life-threatening health problem and is responsible for the high rates of mortality and morbidity in the tropical and subtropical regions of the world. The increasing threat of drug resistance to available artemisinin-based therapy warrants an urgent need to develop new antimalarial drugs that are safer, more effective, and have a novel mode of action. Natural plants are an excellent source of inspiration in searching for a new antimalarial agent. This research reports a systematic investigation for determining the antimalarial potential of the seeds of A. squamosa. The study shows that the crude seed extract (CSE), protein, saponin, and the oily fractions of the seeds were nontoxic at a 2000 mg/kg body weight dose when tested in Wistar rats, thus revealing high safety is classified as class 5. The oily fraction, Annomaal, demonstrated pronounced antimalarial activity with low IC₅₀ (1.25 ± 0.183 μg/mL) against P. falciparum in vitro. The CSE and Annomaal significantly inhibited the growth of P. berghei parasites in vivo with 58.47% and 61.11% chemo suppression, respectively, while the standard drug artemether showed chemo suppression of 66.75%. Furthermore, the study demonstrated that oral administration of Annomaal at a daily dose of 250 mg/kg/day for 3 days was adequate to provide a complete cure to the P. berghei-infected mice. Annomaal thus holds promise as being patient-compliant due to the shorter treatment schedule, eliminating the need for frequent dosing for extended time periods as required by several synthetic antimalarial drugs. Further studies are needed to determine the active compounds in the oily fraction responsible for antimalarial activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

14 pages, 2317 KiB

Open AccessArticle

Lichen-Derived Diffractaic Acid Inhibited Dengue Virus Replication in a Cell-Based System

by Naphat Loeanurit^1,2, Truong Lam Tuong^3,4, Van-Kieu Nguyen^3,5,6, Vipanee Vibulakhaophan^1,7, Kowit Hengphasatporn⁸

, Yasuteru Shigeta⁸

, Si Xian Ho⁹, Justin Jang Hann Chu⁹

, Thanyada Rungrotmongkol^10,11, Warinthorn Chavasiri^3,* and Siwaporn Boonyasuppayakorn^1,*

¹ Center of Excellence in Applied Medical Virology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand

² Interdisciplinary Program in Microbiology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand

³ Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam

⁵ Institute of Fundamental and Applied Sciences, Duy Tan University, Ho Chi Minh City 710000, Vietnam

⁶ Faculty of Natural Sciences, Duy Tan University, Da Nang 550000, Vietnam

⁷ Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

⁸ Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Ibaraki, Japan

⁹ Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore

¹⁰ Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand

¹¹ Biocatalyst and Environmental Biotechnology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

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Molecules 2023, 28(3), 974; https://doi.org/10.3390/molecules28030974 - 18 Jan 2023

Cited by 12 | Viewed by 3250

Abstract

Dengue is a mosquito-borne flavivirus that causes 21,000 deaths annually. Depsides and depsidones of lichens have previously been reported to be antimicrobials. In this study, our objective was to identify lichen-derived depsides and depsidones as dengue virus inhibitors. The 18 depsides and depsidones [...] Read more.

Dengue is a mosquito-borne flavivirus that causes 21,000 deaths annually. Depsides and depsidones of lichens have previously been reported to be antimicrobials. In this study, our objective was to identify lichen-derived depsides and depsidones as dengue virus inhibitors. The 18 depsides and depsidones of Usnea baileyi, Usnea aciculifera, Parmotrema dilatatum, and Parmotrema tsavoense were tested against dengue virus serotype 2. Two depsides and one depsidone inhibited dengue virus serotype 2 without any apparent cytotoxicity. Diffractaic acid, barbatic acid, and Parmosidone C were three active compounds further characterized for their efficacies (EC₅₀), cytotoxicities (CC₅₀), and selectivity index (SI; CC₅₀/EC₅₀). Their EC₅₀ (SI) values were 2.43 ± 0.19 (20.59), 0.91 ± 0.15 (13.33), and 17.42 ± 3.21 (8.95) μM, respectively. Diffractaic acid showed the highest selectivity index, and similar efficacies were also found in dengue serotypes 1–4, Zika, and chikungunya viruses. Cell-based studies revealed that the target was mainly in the late stage with replication and the formation of infectious particles. This report highlights that a lichen-derived diffractaic acid could become a mosquito-borne antiviral lead as its selectivity indices ranged from 8.07 to 20.59 with a proposed target at viral replication. Full article

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30 pages, 2455 KiB

Open AccessReview

Essential Oils as Novel Anthelmintic Drug Candidates

by Sujogya Kumar Panda^1,2,3,*,†

, Marijn Daemen^1,†, Gunanidhi Sahoo^3,*

and Walter Luyten¹

¹ Department of Biology, KU Leuven, 3000 Leuven, Belgium

² Center of Environment Climate Change and Public Health, RUSA 2.0, Utkal University, Bhubaneswar 751004, Odisha, India

³ Department of Zoology, Utkal University, Bhubaneswar 751004, Odisha, India

^† These authors contributed equally to this work.

Molecules 2022, 27(23), 8327; https://doi.org/10.3390/molecules27238327 - 29 Nov 2022

Cited by 20 | Viewed by 7457

Abstract

Helminths, with an estimated 1.5 billion annual global infections, are one of the major health challenges worldwide. The current strategy of the World Health Organization to prevent helminth infection includes increasing hygienic awareness, providing better sanitation and preventative anthelmintic drug therapy in vulnerable [...] Read more.

Helminths, with an estimated 1.5 billion annual global infections, are one of the major health challenges worldwide. The current strategy of the World Health Organization to prevent helminth infection includes increasing hygienic awareness, providing better sanitation and preventative anthelmintic drug therapy in vulnerable populations. Nowadays, anthelmintic drugs are used heavily in livestock, both in case of infection and as a preventative measure. However, this has led to the development of resistance against several of the most common drugs, such as levamisole, ivermectin and thiabendazole. As many as 70% of the livestock in developed countries now has helminths that are drug resistant, and multiple resistance is common. Because of this, novel anthelmintics are urgently needed to help combat large-scale production losses. Prior to this review, no comprehensive review of the anthelmintic effects of essential oils and their components existed. Multiple review articles have been published on the uses of a single plant and its extracts that only briefly touch upon their anthelmintic activity. This review aims to provide a detailed overview of essential oils and their components as anthelmintic treatment against a wider variety of helminths. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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19 pages, 3085 KiB

Open AccessArticle

Effect of Bauhinia monandra Kurz Leaf Preparations on Embryonic Stages and Adult Snails of Biomphalaria glabrata (Say, 1818), Schistosoma mansoni Cercariae and Toxicity in Artemia salina

by Thierry Wesley de Albuquerque Aguiar¹, José Josenildo Batista¹, Silvio Assis de Oliveira Ferreira¹, Maíra de Vasconcelos Lima Sampaio², Dewson Rocha Pereira², Magda Rhayanny Assunção Ferreira³, Luiz Alberto Lira Soares³, Ana Maria Mendonça de Albuquerque Melo², Mônica Camelo Pessoa de Azevedo Albuquerque^4,5, André de Lima Aires^4,5,*

, Hallysson Douglas Andrade de Araújo^1,5,*

and Luana Cassandra Breitenbach Barroso Coelho^1,*

¹ Centro de Biociências, Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Avenida Prof. Moraes Rego, Cidade Universitária, n 1235, Recife 50670-420, PE, Brazil

² Centro de Biociências, Departamento de Biofísica e Radiobiologia, Universidade Federal de Pernambuco (UFPE), Avenida Prof. Moraes Rego, Cidade Universitária, n 1235, Recife 50670-420, PE, Brazil

³ Centro de Ciências da Saúde, Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (UFPE), Avenida Prof. Arthur de Sá, Cidade Universitária, s/n, Recife 50740-521, PE, Brazil

⁴ Centro de Ciências Médicas—Área Acadêmica de Medicina Tropical, Universidade Federal de Pernambuco (UFPE), Avenida Prof. Moraes Rego, Cidade Universitária, n 531-611, Recife 50670-901, PE, Brazil

⁵ Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco (UFPE), Avenida Prof. Moraes Rego, Cidade Universitária, n 1235, Recife 50670-901, PE, Brazil

Molecules 2022, 27(15), 4993; https://doi.org/10.3390/molecules27154993 - 5 Aug 2022

Cited by 9 | Viewed by 2863

Abstract

Biomphalaria glabrata snails constitute the main vector of schistosomiasis in Brazil, and Bauhinia monandra Kurz, the leaves of which contain BmoLL lectin with biocidal action, is a plant widely found on continents in which the disease is endemic. This work describes the composition [...] Read more.

Biomphalaria glabrata snails constitute the main vector of schistosomiasis in Brazil, and Bauhinia monandra Kurz, the leaves of which contain BmoLL lectin with biocidal action, is a plant widely found on continents in which the disease is endemic. This work describes the composition of B. monandra preparations and the effect on embryos and adult snails, their reproduction parameters and hemocytes. We also describe the results of a comet assay after B. glabrata exposure to sublethal concentrations of the preparations. Additionally, the effects of the preparations on S. mansoni cercariae and environmental monitoring with Artemia salina are described. In the chemical evaluation, cinnamic, flavonoid and saponin derivatives were detected in the two preparations assessed, namely the saline extract and the fraction. Both preparations were toxic to embryos in the blastula, gastrula, trochophore, veliger and hippo stages (LC₅₀ of 0.042 and 0.0478; 0.0417 and 0.0419; 0.0897 and 0.1582; 0.3734 and 0.0974; 0.397 and 0.0970 mg/mL, respectively) and to adult snails (LC₅₀ of 6.6 and 0.87 mg/mL, respectively), which were reproductively affected with decreased egg deposition. In blood cell analysis, characteristic cells for apoptosis, micronucleus and binucleation were detected, while for comet analysis, different degrees of nuclear damage were detected. The fraction was able to cause total mortality of the cercariae and did not present environmental toxicity. Therefore, B. monandra preparations are promising in combating schistosomiasis since they can control both the intermediate host and eliminate the infectious agent, besides being safe to the environment. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 1880 KiB

Open AccessArticle

Isolation and Structural Elucidation of Compounds from Pleiocarpa bicarpellata and Their In Vitro Antiprotozoal Activity

by Ozlem Sevik Kilicaslan^1,2, Sylvian Cretton^1,2

, Luis Quirós-Guerrero^1,2

, Merveilles A. Bella³, Marcel Kaiser^4,5, Pascal Mäser^4,5

, Joseph T. Ndongo³ and Muriel Cuendet^1,2,*

¹ School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland

² Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland

³ Department of Chemistry, Higher Teacher Training College, University of Yaoundé 1, Yaoundé P.O. Box 47, Cameroon

⁴ Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland

⁵ University of Basel, 4003 Basel, Switzerland

Molecules 2022, 27(7), 2200; https://doi.org/10.3390/molecules27072200 - 28 Mar 2022

Cited by 7 | Viewed by 3428

Abstract

Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based [...] Read more.

Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based dereplication provided 16 compounds: seven indole alkaloids, four indoline alkaloids, two secoiridoid glycosides, two iridoid glycosides, and one phenolic glucoside. One of the quaternary indole alkaloids (7) and one indoline alkaloid (15) have never been reported before. Their structures were elucidated by analysis of spectroscopic data, including 1D and 2D NMR experiments, UV, IR, and HRESIMS data. The absolute configurations were determined by comparison of the experimental and calculated ECD data. The extracts and isolated compounds were evaluated for their antiprotozoal activity towards Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum, as well as for their cytotoxicity against rat skeletal myoblast L6 cells. The dichloromethane/methanol (1:1) root extract showed strong activity against P. falciparum (IC₅₀ value of 3.5 µg/mL). Among the compounds isolated, tubotaiwine (13) displayed the most significant antiplasmodial activity with an IC₅₀ value of 8.5 µM and a selectivity index of 23.4. Therefore, P. bicarpallata extract can be considered as a source of indole alkaloids with antiplasmodial activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 1157 KiB

Open AccessArticle

In Vitro Pharmacological Screening of Essential Oils from Baccharis parvidentata and Lippia origanoides Growing in Brazil

by Wilmer H. Perera¹

, Alexander M. Scherbakov²

, Galina I. Buravchenko^3,4, Ekaterina I. Mikhaevich², Suzana Guimarães Leitão^5,6

, Paul Cos^6,7

, Andrey E. Shchekotikhin³

, Lianet Monzote^6,8

and William N. Setzer^6,9,10,*

¹ CAMAG Scientific, Inc., 515 Cornelius Harnett Drive, Wilmington, NC 28401, USA

² Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, 24 Kashirskoye sh., 115522 Moscow, Russia

³ Laboratory of Chemical Transformations of Antibiotics, Gause Institute of New Antibiotics, 11 B. Pirogovskaya St., 119021 Moscow, Russia

⁴ Organic Chemistry Department, Faculty of Natural Sciences, Mendeleyev University of Chemical Technology, 9 Miusskaya Square, 125190 Moscow, Russia

⁵ Faculty of Pharmacy, Federal University of Rio de Janeiro, CCS, Bl. A, Ilha do Fundão, Rio de Janeiro 21941-902, Brazil

⁶ Research Network Natural Products against Neglected Diseases (ResNetNPND), University of Münster, 48149 Münster, Germany

⁷ Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Antwerp, Belgium

⁸ Parasitology Department, Institute of Tropical Medicine “Pedro Kouri”, Havana 10400, Cuba

⁹ Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA

¹⁰ Aromatic Plant Research Center, 230 N 1200 E, Suite 100, Lehi, UT 84043, USA

Molecules 2022, 27(6), 1926; https://doi.org/10.3390/molecules27061926 - 16 Mar 2022

Cited by 9 | Viewed by 3011

Abstract

In this study, the in vitro antimicrobial, antiparasitic, antiproliferative and cytotoxic activities of essential oil from Baccharis parvidentata Malag. (EO-Bp) and Lippia origanoides Kunth (EO-Lo) were explored. The relevant effects were observed against the parasitic protozoans Plasmodium falciparum, Trypanosoma cruzi [...] Read more.

In this study, the in vitro antimicrobial, antiparasitic, antiproliferative and cytotoxic activities of essential oil from Baccharis parvidentata Malag. (EO-Bp) and Lippia origanoides Kunth (EO-Lo) were explored. The relevant effects were observed against the parasitic protozoans Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei and Leishmania amazonensis (ranging 0.6 to 39.7 µg/mL) and malignant MCF-7, MCF-7/HT, 22Rv1, and A431 cell lines (ranging 6.1 to 31.5 µg/mL). In parallel, EO-Bp showed better selective indexes in comparison with EO-Lo against peritoneal macrophages from BALB/c mice and MRC-5 cell line. In conclusion, EO-Lo is known to show a wide range of health benefits that could be added as another potential use of this oil with the current study. In the case of EO-Bp, the wide spectrum of its activities against protozoal parasites and malignant cells, as well as its selectivity in comparison with non-malignant cells, could suggest an interesting candidate for further tests as a new therapeutic alternative. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 825 KiB

Open AccessArticle

Dianthiamides A–E, Proline-Containing Orbitides from Dianthus chinensis

by Jin Woo Lee¹

, Jun Gu Kim¹, Jae Sang Han¹, Yong Beom Cho¹, Yu Jin Lee¹, Dongho Lee², Dae Hwan Shin¹, Jin Tae Hong¹

, Mi Kyeong Lee¹

and Bang Yeon Hwang^1,*

¹ College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea

² Department of Plant Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea

Molecules 2021, 26(23), 7275; https://doi.org/10.3390/molecules26237275 - 30 Nov 2021

Cited by 4 | Viewed by 2250

Abstract

Orbitides are plant-derived small cyclic peptides with a wide range of biological activities. Phytochemical investigation of the whole plants of Dianthus chinensis was performed with the aim to discover new bioactive orbitides. Five undescribed proline-containing orbitides, dianthiamides A–E (1–5), [...] Read more.

Orbitides are plant-derived small cyclic peptides with a wide range of biological activities. Phytochemical investigation of the whole plants of Dianthus chinensis was performed with the aim to discover new bioactive orbitides. Five undescribed proline-containing orbitides, dianthiamides A–E (1–5), were isolated from a methanolic extract of Dianthus chinensis. Their structures were elucidated by extensive analysis of 1D and 2D NMR and HRESI–TOF–MS as well as ESI–MS/MS fragmentation data. The absolute configuration of the amino acid residues of compounds 1–5 was determined by Marfey’s method. All compounds were tested for their cytotoxic activity, and dianthiamide A (1) exhibited weak activity against A549 cell line with IC₅₀ value of 47.9 μM. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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14 pages, 2532 KiB

Open AccessArticle

Alkyne-Tagged Apigenin, a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads

by Kowit Hengphasatporn^1,†

, Benyapa Kaewmalai^2,3,†, Somruedee Jansongsaeng^4,†, Vishnu Nayak Badavath^2,†

, Thanaphon Saelee², Thamonwan Chokmahasarn⁴

, Tanatorn Khotavivattana⁴

, Yasuteru Shigeta¹

, Thanyada Rungrotmongkol^5,6 and Siwaporn Boonyasuppayakorn^2,*

¹ Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan

² Applied Medical Virology Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand

³ Interdisciplinary Program in Microbiology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand

⁴ Center of Excellence for Natural Product, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand

⁵ Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

⁶ Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand

^† These authors contributed equally to this work.

Molecules 2021, 26(22), 6967; https://doi.org/10.3390/molecules26226967 - 18 Nov 2021

Cited by 10 | Viewed by 4213

Abstract

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne [...] Read more.

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC₅₀ of 2.36 ± 0.22, and 10.55 ± 3.37 µM, respectively, while the cytotoxicities were similar to the original apigenin at the CC₅₀ of 70.34 ± 11.79, and 82.82 ± 11.68 µM, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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6 pages, 455 KiB

Open AccessArticle

Boswellic Acids Show In Vitro Activity against Leishmania donovani

by Hippolyt L. Greve¹, Marcel Kaiser^2,3, Pascal Mäser^2,3

and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Pharma Campus–Corrensstrasse 48, D-48149 Münster, Germany

² Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4051 Basel, Switzerland

³ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

Molecules 2021, 26(12), 3651; https://doi.org/10.3390/molecules26123651 - 15 Jun 2021

Cited by 7 | Viewed by 2488

Abstract

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from Boswellia serrata resin. 11-keto-β-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against [...] Read more.

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from Boswellia serrata resin. 11-keto-β-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against Leishmania donovani axenic amastigotes along with five further boswellic acid derivatives. 3-O-acetyl-11-keto-β-boswellic acid (AKBA) showed the strongest activity with an IC₅₀ value of 0.88 µM against axenic amastigotes but was inactive against intracellular amastigotes in murine macrophages Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 930 KiB

Open AccessArticle

Salvia officinalis L.: Antitrypanosomal Activity and Active Constituents against Trypanosoma brucei rhodesiense

by Núria Llurba Montesino¹, Marcel Kaiser^2,3, Pascal Mäser^2,3

and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany

² Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4051 Basel, Switzerland

³ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

Molecules 2021, 26(11), 3226; https://doi.org/10.3390/molecules26113226 - 27 May 2021

Cited by 5 | Viewed by 2799

Abstract

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. [...] Read more.

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against Tbr, in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of S. officinalis L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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15 pages, 5013 KiB

Open AccessArticle

Nopol-Based Quinoline Derivatives as Antiplasmodial Agents

by Rogers J. Nyamwihura, Huaisheng Zhang, Jasmine T. Collins, Olamide Crown and Ifedayo Victor Ogungbe^*

Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA

Molecules 2021, 26(4), 1008; https://doi.org/10.3390/molecules26041008 - 14 Feb 2021

Cited by 11 | Viewed by 3165

Abstract

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new [...] Read more.

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2–4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC₅₀ in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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20 pages, 2652 KiB

Open AccessArticle

The Alkaloid-Enriched Fraction of Pachysandra terminalis (Buxaceae) Shows Prominent Activity against Trypanosoma brucei rhodesiense

by Dagmar Flittner¹, Marcel Kaiser^2,3, Pascal Mäser^2,3

, Norberto P. Lopes⁴

and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany

² Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4051 Basel, Switzerland

³ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

⁴ Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Department of Biomolecular Sciences from School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Do Café s/n CEP, 14040-903 Ribeirão Preto-SP, Brazil

Molecules 2021, 26(3), 591; https://doi.org/10.3390/molecules26030591 - 23 Jan 2021

Cited by 10 | Viewed by 2802

Abstract

In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from Holarrhena africana A. DC. (Apocynaceae) and Buxus sempervirens L. (Buxaceae), respectively, are strong and selective antitrypanosomal agents, we have extended these [...] Read more.

In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from Holarrhena africana A. DC. (Apocynaceae) and Buxus sempervirens L. (Buxaceae), respectively, are strong and selective antitrypanosomal agents, we have extended these studies to another plant, related to the latter—namely, Pachysandra terminalis Sieb. and Zucc. (Buxaceae). This species is known to contain aminosteroids similar to those of Holarrhena and structurally related to the aminocycloartanoids of Buxus. The dicholoromethane extract obtained from aerial parts of P. terminalis and, in particular, its alkaloid fraction obtained by acid–base partitioning showed prominent activity against Trypanosoma brucei rhodesiense (Tbr). Activity-guided fractionation along with extended UHPLC-(+)ESI QTOF MS analyses coupled with partial least squares (PLS) regression modelling relating the analytical profiles of various fractions with their bioactivity against Tbr highlighted eighteen constituents likely responsible for the antitrypanosomal activity. Detailed analysis of their (+)ESI mass spectral fragmentation allowed identification of four known constituents of P. terminalis as well as structural characterization of ten further amino-/amidosteroids not previously reported from this plant. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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21 pages, 3628 KiB

Open AccessArticle

Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream Trypanosoma brucei

by Cecilia Ortíz¹, Francesca Moraca^2,†, Marc Laverriere³, Allan Jordan^4,‡

, Niall Hamilton⁴ and Marcelo A. Comini^1,*

¹ Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay

² Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy

³ Instituto de Investigaciones Biotecnológicas, Instituto Tecnológico de Chascomus (IIB-INTECH, UNSAM-CONICET), Av. General Paz 5445, INTI, San Martín 1650, Pcia de Buenos Aires, Argentina

⁴ Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK

^† Current affiliation: Schrödinger, Inc., 120 West 45th Street, New York, NY 10036, USA.

^‡ Current affiliation: Sygnature Discovery, Biocity, Pennyfoot Street, Nottingham NG1 1GR, UK.

Molecules 2021, 26(2), 358; https://doi.org/10.3390/molecules26020358 - 12 Jan 2021

Cited by 12 | Viewed by 3242

Abstract

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH⁺ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, [...] Read more.

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH⁺ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding β-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit μM EC₅₀ against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH⁺-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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10 pages, 1118 KiB

Open AccessArticle

Target-Guided Isolation of O-tigloylcyclovirobuxeine-B from Buxus sempervirens L. by Centrifugal Partition Chromatography

by Lara U. Szabó

and Thomas J. Schmidt^*

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, Pharma Campus Correnstraße 48, D-48149 Münster, Germany

Molecules 2020, 25(20), 4804; https://doi.org/10.3390/molecules25204804 - 19 Oct 2020

Cited by 8 | Viewed by 2692

Abstract

The increasing drug resistance of malaria parasites challenges the treatment of this life-threatening disease. Consequently, the development of innovative and effective antimalarial drugs is inevitable. O-tigloylcyclovirobuxeine-B, a nor-cycloartane alkaloid from Buxussempervirens L., has shown promising and selective in vitro activity [...] Read more.

The increasing drug resistance of malaria parasites challenges the treatment of this life-threatening disease. Consequently, the development of innovative and effective antimalarial drugs is inevitable. O-tigloylcyclovirobuxeine-B, a nor-cycloartane alkaloid from Buxussempervirens L., has shown promising and selective in vitro activity in previous studies against Plasmodiumfalciparum (Pf), causative agent of Malaria tropica. For further investigations, it is indispensable to develop an advanced and efficient isolation procedure of this valuable natural product. Accordingly, we used liquid–liquid chromatography including centrifugal partition chromatography (CPC) to obtain the pure alkaloid on a semi-preparative scale. Identification and characterization of the target compound was accomplished by UHPLC/+ESI-QqTOF-MS/MS, ¹H NMR and ¹³C NMR. In conclusion, this work provides a new and efficient method to obtain O-tigloylcyclovirobuxeine-B, a valuable natural product, as a promising antiplasmodial lead structure for the development of innovative and safe medicinal agents. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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9 pages, 1189 KiB

Open AccessArticle

Apoferritin and Apoferritin-Capped Metal Nanoparticles Inhibit Arginine Kinase of Trypanosoma brucei

by Oluyomi Stephen Adeyemi^1,2,3,*, Afolake T. Arowolo⁴, Helal F. Hetta^5,6

, Salim Al-Rejaie⁷, Damilare Rotimi³

and Gaber El-Saber Batiha⁸

¹ Laboratory of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam

² Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam

³ Nanomedicine & Toxicology Laboratory, Medicinal Biochemistry, Department of Biochemistry, Landmark University, PMB 1001, Omu-Aran 251101, Nigeria

⁴ Hair and Skin Research Laboratory, Division of Dermatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa

⁵ Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt

⁶ Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0595, USA

⁷ Director for KSU Human Resources, Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia

⁸ Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt

Molecules 2020, 25(15), 3432; https://doi.org/10.3390/molecules25153432 - 28 Jul 2020

Cited by 8 | Viewed by 3164

Abstract

The aim of this study was to explore the inhibitory potential of apoferritin or apoferritin-capped metal nanoparticles (silver, gold and platinum) against Trypanosomabrucei arginine kinase. The arginine kinase activity was determined in the presence and absence of apoferritin or apoferritin-capped metal nanoparticles. [...] Read more.

The aim of this study was to explore the inhibitory potential of apoferritin or apoferritin-capped metal nanoparticles (silver, gold and platinum) against Trypanosomabrucei arginine kinase. The arginine kinase activity was determined in the presence and absence of apoferritin or apoferritin-capped metal nanoparticles. In addition, kinetic parameters and relative inhibition of enzyme activity were estimated. Apoferritin or apoferritin-capped metal nanoparticles’ interaction with arginine kinase of T. brucei led to a >70% reduction in the enzyme activity. Further analysis to determine kinetic parameters suggests a mixed inhibition by apoferritin or apoferritin-nanoparticles, with a decrease in V_max. Furthermore, the K_m of the enzyme increased for both ATP and L-arginine substrates. Meantime, the inhibition constant (K_i) values for the apoferritin and apoferritin-nanoparticle interaction were in the submicromolar concentration ranging between 0.062 to 0.168 nM and 0.001 to 0.057 nM, respectively, for both substrates (i.e., L-arginine and ATP). Further kinetic analyses are warranted to aid the development of these nanoparticles as selective therapeutics. Also, more studies are required to elucidate the binding properties of these nanoparticles to arginine kinase of T. brucei. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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12 pages, 1590 KiB

Open AccessArticle

Trypanocidal Activity of Four Sesquiterpene Lactones Isolated from Asteraceae Species

by Orlando G. Elso^1,2,†, Augusto E. Bivona^3,4,†, Andrés Sanchez Alberti^3,5

, Natacha Cerny⁶, Lucas Fabian¹, Celina Morales⁷, César A. N. Catalán⁸, Emilio L. Malchiodi^3,4

, Silvia I. Cazorla^5,9,*,‡ and Valeria P. Sülsen^1,2,*,‡

¹ Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET–Universidad de Buenos Aires, Junín 956 2° floor, Buenos Aires 1113, Argentina

² Cátedra de Farmacognosia, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 2° floor, Buenos Aires 1113, Argentina

³ Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 4° floor, Buenos Aires 1113, Argentina

⁴ Instituto de Estudios de la Inmunidad Humoral (IDEHU), UBA-CONICET. Junín 956 4° floor, Buenos Aires 1113, Argentina

⁵ Instituto de Microbiología y Parasitología Médica—CONICET (IMPaM), Facultad de Medicina, CONICET—Universidad de Buenos Aires, Paraguay 2155. 13° floor, Buenos Aires C1121ABG, Argentina

⁶ Instituto de Ecología y Desarrollo Sustentable (INEDES), CONICET—Universidad Nacional de Luján, Ruta 5 y Avenida Constitución, Luján 6700, Argentina

⁷ Departamento de Patología, Instituto de Fisiopatología Cardiovascular, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires 1113, Argentina

⁸ Instituto de Química del Noroeste—CONICET (INQUINOA), CONICET—Universidad Nacional de Tucumán, Ayacucho 471, San Miguel de Tucumán T4000INI, Argentina

⁹ CONICET—Centro de Referencia para Lactobacilos (CERELA), Batalla de Chacabuco 145. San Miguel de Tucumán T4000INI, Argentina

^† These authors contributed equally to this work.

^‡ The work was co-directed by both authors.

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Molecules 2020, 25(9), 2014; https://doi.org/10.3390/molecules25092014 - 25 Apr 2020

Cited by 23 | Viewed by 4032

Abstract

The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide have been isolated from Argentinean Astearaceae species and have been found to be active against Trypanosoma cruzi epimastigotes. The aim of this work was to evaluate the activity of these compounds by analyzing their [...] Read more.

The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide have been isolated from Argentinean Astearaceae species and have been found to be active against Trypanosoma cruzi epimastigotes. The aim of this work was to evaluate the activity of these compounds by analyzing their effect against the stages of the parasites that are infective for the human. Even more interesting, we aimed to determine the effect of the most active and selective compound on an in vivo model of T. cruzi infection. Eupatoriopicrin was the most active against amastigotes and tripomastigotes (IC₅₀ = 2.3 µg/mL, and 7.2 µg/mL, respectively) and displayed a high selectivity index. This compound was selected to study on an in vivo model of T. cruzi infection. The administration of 1 mg/kg/day of eupatoriopicrin for five consecutive days to infected mice produced a significant reduction in the parasitaemia levels in comparison with non-treated animals (area under parasitaemia curves 4.48 vs. 30.47, respectively). Skeletal muscular tissues from eupatopicrin-treated mice displayed only focal and interstitial lymphocyte inflammatory infiltrates and small areas of necrotic; by contrast, skeletal tissues from T. cruzi infected mice treated with the vehicle showed severe lymphocyte inflammatory infiltrates with necrosis of the adjacent myocytes. The results indicate that eupatoriopicrin could be considered a promising candidate for the development of new therapeutic agents for Chagas disease. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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9 pages, 916 KiB

Open AccessFeature PaperArticle

Efficacy of Topical Treatment with (−)-Epigallocatechin Gallate, A Green Tea Catechin, in Mice with Cutaneous Leishmaniasis

by Andrea M. Sosa¹, Agustín Moya Álvarez¹

, Estefanía Bracamonte¹, Masataka Korenaga^2,3, Jorge D. Marco¹ and Paola A. Barroso^1,*

¹ Instituto de Patología Experimental, Facultad de Ciencias de la Salud, Universidad Nacional de Salta-CONICET, Salta 4400, Argentina

² Department of Parasitology, Kochi Medical School, Kochi University, Okocho Kohasu, Nankoku, Kochi Prefecture 783-8505, Japan

³ Faculty of Health Sciences, Kochi Gakuen University, Asahi-Tenjincho, Kochi, Kochi Prefecture 780-0955, Japan

Molecules 2020, 25(7), 1741; https://doi.org/10.3390/molecules25071741 - 10 Apr 2020

Cited by 16 | Viewed by 3609

Abstract

The treatment of leishmaniasis includes pentavalent antimony drugs but, because of the side effects, toxicity and cases of treatment failure or resistance, the search of new antileishmanial compounds are necessary. The aims of this study were to evaluate and compare the in vitro [...] Read more.

The treatment of leishmaniasis includes pentavalent antimony drugs but, because of the side effects, toxicity and cases of treatment failure or resistance, the search of new antileishmanial compounds are necessary. The aims of this study were to evaluate and compare the in vitro antileishmanial activity of four green tea catechins, and to assess the efficacy of topical (−)-epigallocatechin gallate in a cutaneous leishmaniasis model. The antileishmanial activity of green tea catechins was evaluated against intracellular amastigotes, and cytotoxicity was performed with human monocytic cell line. BALB/c mice were infected in the ear dermis with Leishmania (Leishmania) amazonensis and treated with topical 15% (−)-epigallocatechin gallate, intraperitoneal Glucantime, and control group. The efficacy of treatments was evaluated by quantifying the parasite burden and by measuring the lesions size. (−)-Epigallocatechin gallate and (−)-epigallocatechin were the most active compounds with IC₅₀ values <59.6 µg/mL and with a selectivity index >1. Topical treatment with (−)-epigallocatechin gallate decreased significantly both lesion size and parasite burden (80.4% inhibition) compared to control group (p < 0.05), and moreover (−)-epigallocatechin gallate showed a similar efficacy to Glucantime (85.1% inhibition), the reference drug for leishmaniasis treatment. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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16 pages, 479 KiB

Open AccessArticle

Antiprotozoal Activity of Turkish Origanum onites Essential Oil and Its Components

by Deniz Tasdemir^1,2,3,*

, Marcel Kaiser^4,5, Betül Demirci⁶, Fatih Demirci⁶

and K. Hüsnü Can Baser^6,7

¹ Department of Pharmaceutical and Biological Chemistry, Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, London WC1N 1AX, UK

² GEOMAR Centre for Marine Biotechnology, Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, 24106 Kiel, Germany

³ Kiel University, Christian-Albrechts-Platz 4, 24118 Kiel, Germany

⁴ Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland

⁵ University of Basel, 4003 Basel, Switzerland

⁶ Department of Pharmacognosy, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey

⁷ Department of Pharmacognosy, Faculty of Pharmacy, Near East University, 99138 Nicosia, N. Cyprus

Molecules 2019, 24(23), 4421; https://doi.org/10.3390/molecules24234421 - 3 Dec 2019

Cited by 50 | Viewed by 9202

Abstract

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of [...] Read more.

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of parasitic protozoa. The essential oil was obtained by hydrodistillation from the dried herbal parts of O. onites and analyzed by Gas Chromatography-Flame Ionization Detector (GC-FID) and Gas Chromatography coupled with Mass Spectrometry (GC-MS). The in vitro activity of the oil and its major components were evaluated against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. The main component of the oil was identified as carvacrol (70.6%), followed by linalool (9.7%), p-cymene (7%), γ-terpinene (2.1%), and thymol (1.8%). The oil showed significant in vitro activity against T. b. rhodesiense (IC₅₀ 180 ng/mL), and moderate antileishmanial and antiplasmodial effects, without toxicity to mammalian cells. Carvacrol, thymol, and 10 additional abundant oil constituents were tested against the same panel; carvacrol and thymol retained the oil’s in vitro antiparasitic potency. In the T. b. brucei mouse model, thymol, but not carvacrol, extended the mean survival of animals. This study indicates the potential of the essential oil of O. onites and its constituents in the treatment of protozoal infections. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 465 KiB

Open AccessArticle

Bixa orellana L. (Bixaceae) and Dysphania ambrosioides (L.) Mosyakin & Clemants (Amaranthaceae) Essential Oils Formulated in Nanocochleates against Leishmania amazonensis

by Laura Machín¹, Beatriz Tamargo², Abel Piñón³, Regla C. Atíes¹, Ramón Scull¹, William N. Setzer^4,5,6,*

and Lianet Monzote^3,6,*

¹ Department of Pharmacy, Institute of Pharmacy and Food, Havana University, Havana 17100, Cuba

² Department of Physiological Science, Latin American School of Medical Sciences, Havana 11300, Cuba

³ Department of Parasitology, Institute of Tropical Medicine Pedro Kourí, Havana 17100, Cuba

⁴ Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA

⁵ Aromatic Plant Research Center, 230 N 1200 E, Suite 100, Lehi, UT 84043, USA

⁶ Research Network: Natural Products against Neglected Diseases (ResNet NPND)

Molecules 2019, 24(23), 4222; https://doi.org/10.3390/molecules24234222 - 20 Nov 2019

Cited by 19 | Viewed by 3728

Abstract

Leishmaniasis is a group of neglected tropical diseases caused by protozoan parasites of the Leishmania genus. The absence of effective vaccines and the limitations of current treatments make the search for effective therapies a real need. Different plant-derived essential oils (EOs) have shown [...] Read more.

Leishmaniasis is a group of neglected tropical diseases caused by protozoan parasites of the Leishmania genus. The absence of effective vaccines and the limitations of current treatments make the search for effective therapies a real need. Different plant-derived essential oils (EOs) have shown antileishmanial effects, in particular from Bixa orellana L. (EO-Bo) and Dysphania ambrosioides (L.) Mosyakin & Clemants (EO-Da). In the present study, the EO-Bo and EO-Da, formulated in nanocochleates (EO-Bo-NC and EO-Da-NC, respectively), were evaluated in vitro and in vivo against L. amazonensis. The EO-Bo-NC and EO-Da-NC did not increase the in vitro inhibitory activity of the EOs, although the EO-Bo-NC showed reduced cytotoxic effects. In the animal model, both formulations (30 mg/kg/intralesional route/every 4 days/4 times) showed no deaths or weight loss greater than 10%. In the animal (mouse) model, EO-Bo-NC contributed to the control of infection (p < 0.05) in comparison with EO-Bo treatment, while the mice treated with EO-Da-NC exhibited larger lesions (p < 0.05) compared to those treated with EO-Da. The enhanced in vivo activity observed for EO-Bo-NC suggests that lipid-based nanoformulations like nanocochleates should be explored for their potential in the proper delivery of drugs, and in particular, the delivery of hydrophobic materials for effective cutaneous leishmaniasis treatment. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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20 pages, 4278 KiB

Open AccessReview

The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines

by Luiz C. S. Pinheiro¹

, Lívia M. Feitosa^1,2, Marilia O. Gandi^1,2, Flávia F. Silveira^1,3 and Nubia Boechat^1,2,3,*

¹ Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos-FIOCRUZ, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro 21041-250, Brazil

² Programa de Pós-Graduação em Farmacologia e Química Medicinal, PPGFQM, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21041-250, Brazil

³ Programa de Pós-Graduação em Química, PGQu Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21041-250, Brazil

Molecules 2019, 24(22), 4095; https://doi.org/10.3390/molecules24224095 - 13 Nov 2019

Cited by 62 | Viewed by 6378

Abstract

Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in [...] Read more.

Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plasmodium berghei-infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine–atorvastatin and primaquine–atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype I that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the P. falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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22 pages, 8599 KiB

Open AccessArticle

A Nature-Inspired Design Yields a New Class of Steroids Against Trypanosomatids

by Elena Aguilera^1,†, Cintya Perdomo^2,†, Alejandra Espindola², Ileana Corvo², Paula Faral-Tello³, Carlos Robello^3,4

, Elva Serna⁵, Fátima Benítez^5,6, Rocío Riveros^5,6, Susana Torres⁵, Ninfa I. Vera de Bilbao⁵, Gloria Yaluff^5,* and Guzmán Alvarez^2,*

¹ Grupo de Química Medicinal-Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo C.P. 11400, Uruguay

² Laboratorio de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la República, Ruta 3 (km 363), Paysandú C.P. 60000, Uruguay

³ Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo C.P. 11400, Uruguay

⁴ Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11200, Uruguay

⁵ Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, San Lorenzo C.P. 2169., Paraguay

⁶ Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Asunción, San Lorenzo C.P. 2169., Paraguay

^† Both authors contributed equally to this work.

Molecules 2019, 24(20), 3800; https://doi.org/10.3390/molecules24203800 - 22 Oct 2019

Cited by 13 | Viewed by 5039

Abstract

Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic [...] Read more.

Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic activity were isolated from diverse organisms (ticks, plants, fungi). These molecules have complex structures that make de novo synthesis extremely difficult. In this work, we designed new and simpler compounds with antiparasitic potential inspired in natural steroids and synthesized a series of nineteen steroidal arylideneketones and thiazolidenehydrazines. We explored their biological activity against Leishmania infantum, Leishmania amazonensis, and Trypanosoma cruzi in vitro and in vivo. We also assayed their genotoxicity and acute toxicity in vitro and in mice. The best compound, a steroidal thiosemicarbazone compound 8 (ID_1260) was active in vitro (IC₅₀ 200 nM) and in vivo (60% infection reduction at 50 mg/kg) in Leishmania and T. cruzi. It also has low toxicity in vitro and in vivo (LD₅₀ >2000 mg/kg) and no genotoxic effects, being a promising compound for anti-trypanosomatid drug development. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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16 pages, 2907 KiB

Open AccessArticle

Larvicidal Compounds Extracted from Helicteres velutina K. Schum (Sterculiaceae) Evaluated against Aedes aegypti L.

by Diégina A. Fernandes¹

, Renata P. C. Barros¹, Yanna C. F. Teles²

, Louise H. G. Oliveira³, Jéssica B. Lima⁴, Marcus T. Scotti¹

, Fabíola C. Nunes³, Adilva S. Conceição⁴ and Maria de Fátima Vanderlei de Souza^1,5,*

¹ Post graduation Program in Bioactive Natural and Synthetic Products, Research Institute for Drugs and Medicines (IPeFarM), Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil

² Department of Chemistry and Physics, Agrarian Sciences Center, Federal University of Paraíba, 58397-000 Areia, PB, Brazil

³ Biotechnology Center, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil

⁴ Post graduation Program in Plant Biodiversity, Department of Education, University of the State of Bahia, 41150-000 Paulo Afonso, BA, Brazil

⁵ Post graduation in Development and Technological Innovation in Medicines, Research Institute for Drugs and Medicines (IPeFarM), Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil

Molecules 2019, 24(12), 2315; https://doi.org/10.3390/molecules24122315 - 22 Jun 2019

Cited by 21 | Viewed by 5830

Abstract

Helicteres velutina K. Schum (Sterculiaceae), a member of Malvaceae sensu lato, is a Brazilian endemic plant that has been used by the indigenous tribe Pankarare as an insect repellent. A previous study has reported the isolation of terpenoids, flavonoids and pheophytins, in [...] Read more.

Helicteres velutina K. Schum (Sterculiaceae), a member of Malvaceae sensu lato, is a Brazilian endemic plant that has been used by the indigenous tribe Pankarare as an insect repellent. A previous study has reported the isolation of terpenoids, flavonoids and pheophytins, in addition to the larvicidal activity of crude H. velutina extracts derived from the aerial components (leaves, branches/twigs, and flowers). The present study reports the biomonitoring of the effects of fractions and isolated compounds derived from H. velutina against A. aegypti fourth instar larvae. A crude ethanol extract was submitted to liquid–liquid extraction with hexane, dichloromethane, ethyl acetate and n-butanol to obtain their respective fractions. Larvicidal evaluations of the fractions were performed, and the hexane and dichloromethane fractions exhibited greater activities than the other fractions, with LC₅₀ (50% lethal concentration) values of 3.88 and 5.80 mg/mL, respectively. The phytochemical study of these fractions resulted in the isolation and identification of 17 compounds. The molecules were subjected to a virtual screening protocol, and five molecules presented potential larvicidal activity after analyses of their applicability domains. When molecular docking was analysed, only three of these compounds showed an ability to bind with sterol carrier protein-2 (1PZ4), a protein found in the larval intestine. The compounds tiliroside and 7,4′-di-O-methyl-8-O-sulphate flavone showed in vitro larvicidal activity, with LC₅₀ values of 0.275 mg/mL after 72 h and 0.182 mg/mL after 24 h of exposure, respectively. This is the first study to demonstrate the larvicidal activity of sulphated flavonoids against A. aegypti. Our results showed that the presence of the OSO₃H group attached to C-8 of the flavonoid was crucial to the larvicidal activity. This research supports the traditional use of H. velutina as an alternative insecticide for the control of A. aegypti, which is a vector for severe arboviruses, such as dengue and chikungunya. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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11 pages, 775 KiB

Open AccessArticle

Chemical Composition, Antimicrobial and Antiparasitic Screening of the Essential Oil from Phania matricarioides (Spreng.) Griseb.

by Yamilet I. Gutiérrez¹, Ramón Scull¹, Anabel Villa², Prabodh Satyal³

, Paul Cos^4,5, Lianet Monzote^5,6,* and William N. Setzer^3,5,7,*

¹ Department of Pharmacy, Institute of Pharmacy and Food, Havana University, Coronela, Lisa, Havana 13600, Cuba

² Genetic toxicology and antitumor laboratory, Drug Research and Development Center (CIDEM), Havana 10600, Cuba

³ Aromatic Plant Research Center, 230 N 1200 E, Suite 100, Lehi, UT 84043, USA

⁴ Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium

⁵ Research Network Natural Products against Neglected Diseases (ResNet NPND)

⁶ Parasitology Department, Center of Research, Diagnostic and Reference, Institute of Tropical Medicine “Pedro Kouri”, Havana 10400, Cuba

⁷ Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA

Molecules 2019, 24(8), 1615; https://doi.org/10.3390/molecules24081615 - 24 Apr 2019

Cited by 11 | Viewed by 4795

Abstract

Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against [...] Read more.

Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against a wide panel of bacteria, fungi and parasitic protozoa. Forty-five compounds were identified in the studied EO, of which lavandulyl acetate (40.1%) and thymyl isobutyrate (13.9%) were the major components. The EO did not inhibit bacterial or fungal growth at the maximum concentration tested (64 µg/mL), although it displayed activity on all evaluated protozoa (IC₅₀ values ranging from 2.2 to 56.6 µg/mL). In parallel, the EO demonstrated a noteworthy cytotoxic activity against peritoneal macrophages (CC₅₀ values of 28.0 µg/mL). The most sensitive microorganism was Trypanosoma cruzi, which had a superior activity (IC₅₀ = 2.2 µg/mL) and selectivity (SI = 13) in respect to other parasitic protozoa and the reference drug (p < 0.05). Further in vivo studies are needed to evaluate the potential use of this EO and the main compounds as antitrypanosomal agents. To our knowledge, this is the first report of chemical characterization and antimicrobial assessment of the EO from P. matricarioides. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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13 pages, 2010 KiB

Open AccessArticle

Chemical Constituents of Anacardium occidentale as Inhibitors of Trypanosoma cruzi Sirtuins

by Tanira Matutino Bastos¹

, Helena Mannochio Russo²

, Nilmar Silvio Moretti³

, Sergio Schenkman³, Laurence Marcourt², Mahabir Prashad Gupta⁴, Jean-Luc Wolfender²

, Emerson Ferreira Queiroz²

and Milena Botelho Pereira Soares^1,*

¹ Instituto Gonçalo Moniz, FIOCRUZ, Salvador, BA 40296-710, Brazil

² School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU, 1, Rue Michel Servet, 1211 Geneva, Switzerland

³ Departmento de Microbiologia, Imunologia e Parasitologia, UNIFESP, São Paulo, SP 04039-032, Brazil

⁴ Center for Pharmacognostic Research on Panamanian Flora (CIFLORPAN), College of Pharmacy, University of Panama, Panama 0824-00172, Panama

Molecules 2019, 24(7), 1299; https://doi.org/10.3390/molecules24071299 - 3 Apr 2019

Cited by 26 | Viewed by 5966

Abstract

Benznidazole and nifurtimox, the only drugs available for the treatment of Chagas disease, have limited efficacy and have been associated with severe adverse side effects. Thus, there is an urgent need to find new biotargets for the identification of novel bioactive compounds against [...] Read more.

Benznidazole and nifurtimox, the only drugs available for the treatment of Chagas disease, have limited efficacy and have been associated with severe adverse side effects. Thus, there is an urgent need to find new biotargets for the identification of novel bioactive compounds against the parasite and with low toxicity. Silent information regulator 2 (Sir2) enzymes, or sirtuins, have emerged as attractive targets for the development of novel antitrypanosomatid agents. In the present work, we evaluated the inhibitory effect of natural compounds isolated from cashew nut (Anacardium occidentale, L. Anacardiaceae) against the target enzymes TcSir2rp1 and TcSir2rp3 as well as the parasite. Two derivates of cardol (1, 2), cardanol (3, 4), and anacardic acid (5, 6) were investigated. The two anacardic acids (5, 6) inhibited both TcSir2rp1 and TcSir2rp3, while the cardol compound (2) inhibited only TcSir2rp1. The most potent sirtuin inhibitor active against the parasite was the cardol compound (2), with an EC₅₀ value of 12.25 µM, similar to that of benznidazole. Additionally, compounds (1, 4), which were inactive against the sirtuin targets, presented anti-T. cruzi effects. In conclusion, our results showed the potential of Anacardium occidentale compounds for the development of potential sirtuin inhibitors and anti-Trypanosoma cruzi agents. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 427 KiB

Open AccessArticle

In-Vitro Evaluation of 52 Commercially-Available Essential Oils Against Leishmania amazonensis

by Lianet Monzote¹, Isabel Herrera¹, Prabodh Satyal²

and William N. Setzer^2,3,*

¹ Parasitology Department, Institute of Tropical Medicine “Pedro Kouri”, Havana 10400, Cuba

² Aromatic Plant Research Center, 230 N 1200 E, Suite 100, Lehi, UT 84043, USA

³ Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA

Molecules 2019, 24(7), 1248; https://doi.org/10.3390/molecules24071248 - 30 Mar 2019

Cited by 25 | Viewed by 4420

Abstract

Leishmaniasis is a neglected tropical disease caused by members of the Leishmania genus of parasitic protozoa that cause different clinical manifestations of the disease. Current treatment options for the cutaneous disease are limited due to severe side effects, poor efficacy, limited availability or [...] Read more.

Leishmaniasis is a neglected tropical disease caused by members of the Leishmania genus of parasitic protozoa that cause different clinical manifestations of the disease. Current treatment options for the cutaneous disease are limited due to severe side effects, poor efficacy, limited availability or accessibility, and developing resistance. Essential oils may provide low cost and readily available treatment options for leishmaniasis. In-vitro screening of a collection of 52 commercially available essential oils has been carried out against promastigotes of Leishmania amazonensis. In addition, cytotoxicity has been determined for the essential oils against mouse peritoneal macrophages in order to determine selectivity. Promising essential oils were further screened against intracellular L. amazonensis amastigotes. Three essential oils showed notable antileishmanial activities: frankincense (Boswellia spp.), coriander (Coriandrum sativum L.), and wintergreen (Gualtheria fragrantissima Wall.) with IC₅₀ values against the amastigotes of 22.1 ± 4.2, 19.1 ± 0.7, and 22.2 ± 3.5 μg/mL and a selectivity of 2, 7, and 6, respectively. These essential oils could be explored as topical treatment options for cutaneous leishmaniasis. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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13 pages, 1055 KiB

Open AccessArticle

Activity of Estafietin and Analogues on Trypanosoma cruzi and Leishmania braziliensis

by Valeria P. Sülsen^1,2,*,†, Emilio F. Lizarraga^3,†

, Orlando G. Elso^1,2, Natacha Cerny⁴

, Andrés Sanchez Alberti^5,6,7

, Augusto E. Bivona^5,6,7, Emilio L. Malchiodi^5,6,7, Silvia I. Cazorla^7,8 and César A. N. Catalán^9,*

¹ CONICET—Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956 2° floor, Buenos Aires 1113, Argentina

² Cátedra de Farmacognosia, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 2° floor, Buenos Aires 1113, Argentina

³ Instituto de Fisiología Animal, Fundación Miguel Lillo and Facultad de Ciencias Naturales e Instituto Miguel Lillo, Universidad Nacional de Tucumán, Tucumán T4000INI, Argentina

⁴ CONICET—Universidad Nacional de Luján, Instituto de Ecología y Desarrollo Sustentable (INEDES), Ruta 5 y Avenida Constitución, Luján 6700, Argentina

⁵ Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 4° floor, Buenos Aires 1113, Argentina

⁶ Instituto de Estudios de la Inmunidad Humoral (IDEHU), UBA-CONICET, Junín 956 4° floor, Buenos Aires 1113, Argentina

⁷ CONICET—Universidad de Buenos Aires, Instituto de Microbiología y Parasitología Médica—CONICET (IMPaM), Facultad de Medicina, Paraguay 2155. 13° floor, Buenos Aires C1121ABG, Argentina

⁸ CONICET—Centro de Referencia para Lactobacilos (CERELA), Batalla de Chacabuco 145, San Miguel de Tucumán T4000INI, Argentina

⁹ CONICET—Universidad Nacional de Tucumán, Instituto de Química del Noroeste—CONICET (INQUINOA), Ayacucho 471, San Miguel de Tucumán T4000INI, Argentina

^† These authors contributed equally to this work.

Molecules 2019, 24(7), 1209; https://doi.org/10.3390/molecules24071209 - 28 Mar 2019

Cited by 20 | Viewed by 4075

Abstract

Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (1 [...] Read more.

Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (1), isolated from Stevia alpina (Asteraceae): 11βH,13-dihydroestafietin (2), epoxyestafietin (3a and 3b), 11βH,13-methoxyestafietin, (4) and 11βH,13-cianoestafietin. The antiprotozoal activity against Trypanosoma cruzi and Leishmania braziliensis of these compounds was evaluated. Epoxyestafietin was the most active compound against T. cruzi trypomastigotes and amastigotes (IC₅₀ values of 18.7 and 2.0 µg/mL, respectively). Estafietin (1) and 11βH,13-dihydroestafietin (2) were the most active and selective compounds on L. braziliensis promastigotes (IC₅₀ values of 1.0 and 1.3 μg/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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8 pages, 718 KiB

Open AccessArticle

Antitrypanosomal Activity of Sesquiterpene Lactones from Helianthus tuberosus L. Including a New Furanoheliangolide with an Unusual Structure

by Anna Galkina¹, Nico Krause¹, Mairin Lenz¹, Constantin G. Daniliuc²

, Marcel Kaiser^3,4 and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus–Corrensstrasse 48, D-48149 Münster, Germany

² Institute of Organic Chemistry, University of Münster, Corrensstraße 40, D-48149 Münster, Germany

³ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4051 Basel, Switzerland

⁴ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

Molecules 2019, 24(6), 1068; https://doi.org/10.3390/molecules24061068 - 18 Mar 2019

Cited by 8 | Viewed by 4741

Abstract

As part of our efforts to exploit the antitrypanosomal potential of sesquiterpene lactones (STL) from Helianthus tuberosus L. (Asteraceae), besides the known 4,15-iso-atriplicolide tiglate, -methacrylate and -isobutyrate, a hitherto unknown STL was isolated. Its structure was solved by extensive NMR measurements [...] Read more.

As part of our efforts to exploit the antitrypanosomal potential of sesquiterpene lactones (STL) from Helianthus tuberosus L. (Asteraceae), besides the known 4,15-iso-atriplicolide tiglate, -methacrylate and -isobutyrate, a hitherto unknown STL was isolated. Its structure was solved by extensive NMR measurements and confirmed by single crystal X-ray crystallography. This novel compound is a structural analog 4,15-iso-atriplicolide tiglate that possesses the same basic furanoheliangolide skeleton but differs in the position of the oxo function which is at C-2 instead of C-1, as well as in the fact that the oxygen atom of the furanoid ring is part of a hemiketal structure at C-3 and a double bond between C-5 and C-6. For this new STL we propose the name heliantuberolide-8-O-tiglate. Its activity against Trypanosoma brucei rhodesiense (causative agent of East African Human Typanosomiasis, Trypanosoma cruzi (Chagas Disease), Leishmania donovani (Visceral Leishmaniasis) and Plasmodium falciparum (Tropical Malaria) as well as cytotoxicity against rat skeletal myoblasts (L6 cell line) was determined along with those of the hitherto untested 4,15-iso-atriplicolide methacrylate and isobutyrate. In comparison with the iso-atriplicolide esters, the new compound showed a much lower level of bioactivity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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13 pages, 3290 KiB

Open AccessArticle

Antileishmanial Activity of Dimeric Flavonoids Isolated from Arrabidaea brachypoda

by Vinícius P. C. Rocha¹

, Cláudia Quintino da Rocha²

, Emerson Ferreira Queiroz³, Laurence Marcourt³, Wagner Vilegas⁴, Gabriela B. Grimaldi¹

, Pascal Furrer³, Éric Allémann³, Jean-Luc Wolfender³

and Milena B. P. Soares^1,*

¹ Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Avenida Waldemar Falcão, 121, Candeal–Salvador-BA 40296-710, Brazil

² Departamento de Química, Universidade Federal do Maranhão, São Luiz 65080-805, MA, Brazil

³ School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU, 1, Rue Michel Servet, 1211 Geneva, Switzerland

⁴ UNESP-Campus Experimental do Litoral Paulista, Praça Infante Dom Henrique s/n°, Parque Bitaru, São Vicente–SP 11330-900, Brazil

Molecules 2019, 24(1), 1; https://doi.org/10.3390/molecules24010001 - 20 Dec 2018

Cited by 33 | Viewed by 6055

Abstract

Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs [...] Read more.

Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from Arrabidaea brachypoda. Three compounds were tested against Leishmana sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of L. amazonensis, without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in L. amazonensis-infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against Leishmania. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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21 pages, 4915 KiB

Open AccessArticle

Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches

by Shailima Rampogu^†, Gihwan Lee^†, Ayoung Baek, Minky Son, Chanin Park, Amir Zeb, Sang Hwa Yoon, Suhyeon Park and Keun Woo Lee^*

¹ Division of Life Science, Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea

^† These authors contributed equally to this work.

Molecules 2018, 23(12), 3054; https://doi.org/10.3390/molecules23123054 - 22 Nov 2018

Cited by 6 | Viewed by 3536

Abstract

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop [...] Read more.

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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19 pages, 1559 KiB

Open AccessArticle

Solvent Extraction and Identification of Active Anticariogenic Metabolites in Piper cubeba L. through ¹H-NMR-Based Metabolomics Approach

by Raja Nur Asila Raja Mazlan¹, Yaya Rukayadi^1,2,*, M. Maulidiani¹ and Intan Safinar Ismail^1,3

¹ Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia

² Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Malaysia

³ Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang 43400, Malaysia

Molecules 2018, 23(7), 1730; https://doi.org/10.3390/molecules23071730 - 16 Jul 2018

Cited by 10 | Viewed by 5636

Abstract

The aim of this study was to determine the effects of different solvents for extraction, liquid–liquid partition, and concentrations of extracts and fractions of Piper cubeba L. on anticariogenic; antibacterial and anti-inflammatory activity against oral bacteria. Furthermore, ¹H-Nuclear Magnetic Resonance (NMR) coupled [...] Read more.

The aim of this study was to determine the effects of different solvents for extraction, liquid–liquid partition, and concentrations of extracts and fractions of Piper cubeba L. on anticariogenic; antibacterial and anti-inflammatory activity against oral bacteria. Furthermore, ¹H-Nuclear Magnetic Resonance (NMR) coupled with multivariate data analysis (MVDA) was applied to discriminate between the extracts and fractions and examine the metabolites that correlate to the bioactivities. All tested bacteria were susceptible to Piper cubeba L. extracts and fractions. Different solvents extraction, liquid–liquid partition and concentrations of extracts and fractions have partially influenced the antibacterial activity. MTT assay showed that P. cubeba L. extracts and fractions were not toxic to RAW 264.7 cells at selected concentrations. Anti-inflammatory activity evaluated by nitric oxide (NO) production in lipopolysaccharide (LPS) stimulated cells showed a reduction in NO production in cells treated with P. cubeba L. extracts and fractions, compared to those without treatment. Twelve putative metabolites have been identified, which are (1) cubebin, (2) yatein, (3) hinokinin, (4) dihydrocubebin, (5) dihydroclusin, (6) cubebinin, (7) magnosalin, (8) p-cymene, (9) piperidine, (10) cubebol, (11) d-germacrene and (12) ledol. Different extraction and liquid–liquid partition solvents caused separation in principal component analysis (PCA) models. The partial least squares (PLS) models showed that higher anticariogenic activity was related more to the polar solvents, despite some of the active metabolites also present in the non-polar solvents. Hence, P. cubeba L. extracts and fractions exhibited antibacterial and anti-inflammatory activity and have potential to be developed as the anticariogenic agent. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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16 pages, 4334 KiB

Open AccessArticle

Antischistosomal Properties of Hederacolchiside A1 Isolated from Pulsatilla chinensis

by Naixin Kang¹, Wenhua Shen², Hongwei Gao³, Yulin Feng², Weifeng Zhu², Shilin Yang^1,2, Yanli Liu^4,*, Qiongming Xu^1,* and Di Yu⁵

¹ Department of Pharmacognosy, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China

² College of Pharmaceutical Science, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China

³ College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530001, China

⁴ Department of Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China

⁵ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala 75105, Sweden

Molecules 2018, 23(6), 1431; https://doi.org/10.3390/molecules23061431 - 13 Jun 2018

Cited by 24 | Viewed by 4669

Abstract

Background: Schistosomiasis is a major neglected disease for which the current control strategy involves mass treatment with praziquantel, the only available drug. Hence, there is an urgent need to develop new antischistosomal compounds. Methods: The antischistosomal activity of hederacolchiside A1 (HSA) [...] Read more.

Background: Schistosomiasis is a major neglected disease for which the current control strategy involves mass treatment with praziquantel, the only available drug. Hence, there is an urgent need to develop new antischistosomal compounds. Methods: The antischistosomal activity of hederacolchiside A1 (HSA) were determined by total or female worm burden reductions in mice harboring Schistosoma japonicum or S. mansoni. Pathology parameters were detected on HSA against 1-day-old S. japonicum-harboring mice. Moreover, we confirmed the antischistosomal effect of HSA on newly transformed schistosomula (NTS) of S. japonicum in vitro. Results: HSA, a natural product isolated from Pulsatilla chinensis (Bunge) Regel, was initially corroborated to possess promising antischistosomal properties. We demonstrated that HSA had high activity against S. japonicum and S. mansoni less in 11 days old parasites harbored in mice. The antischistosomal effect was even more than the currently used drugs, praziquantel, and artesunate. Furthermore, HSA could ameliorate the pathology parameters in mice harboring 1-day-old juvenile S. japonicum. We also confirmed that HSA-mediated antischistosomal activity is partly due to the morphological changes in the tegument system when NTS are exposed to HSA. Conclusions: HSA may have great potential to be an antischistosomal agent for further research. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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13 pages, 24485 KiB

Open AccessArticle

Anti-Inflammatory Effects of Fargesin on Chemically Induced Inflammatory Bowel Disease in Mice

by Bei Yue^†

, Yi-Jing Ren^†, Jing-Jing Zhang^†, Xiao-Ping Luo, Zhi-Lun Yu, Gai-Yan Ren, A-Ning Sun

, Chao Deng, Zheng-Tao Wang^* and Wei Dou^*

¹ Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

^† These authors contributed equally to this paper.

Molecules 2018, 23(6), 1380; https://doi.org/10.3390/molecules23061380 - 7 Jun 2018

Cited by 39 | Viewed by 6100

Abstract

Fargesin is a bioactive lignan from Flos Magnoliae, an herb widely used in the treatment of allergic rhinitis, sinusitis, and headache in Asia. We sought to investigate whether fargesin ameliorates experimental inflammatory bowel disease (IBD) in mice. Oral administration of fargesin significantly [...] Read more.

Fargesin is a bioactive lignan from Flos Magnoliae, an herb widely used in the treatment of allergic rhinitis, sinusitis, and headache in Asia. We sought to investigate whether fargesin ameliorates experimental inflammatory bowel disease (IBD) in mice. Oral administration of fargesin significantly attenuated the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration and myeloperoxidase (MPO) activity, reducing tumor necrosis factor (TNF)-α secretion, and inhibiting nitric oxide (NO) production in colitis mice. The degradation of inhibitory κBα (IκBα), phosphorylation of p65, and mRNA expression of nuclear factor κB (NF-κB) target genes were inhibited by fargesin treatment in the colon of the colitis mice. In vitro, fargesin blocked the nuclear translocation of p-p65, downregulated the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and dose-dependently inhibited the activity of NF-κB-luciferase in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Taken together, for the first time, the current study demonstrated the anti-inflammatory effects of fargesin on chemically induced IBD might be associated with NF-κB signaling suppression. The findings may contribute to the development of therapies for human IBD by using fargesin or its derivatives. Full article

(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)

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12 pages, 4724 KiB

Open AccessArticle

A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis

by Charles Okeke Nnadi^1,2

, Julia Barbara Althaus¹, Ngozi Justina Nwodo²

and Thomas Jürgen Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany

² Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State 410001, Nigeria

Molecules 2018, 23(5), 1113; https://doi.org/10.3390/molecules23051113 - 8 May 2018

Cited by 18 | Viewed by 6026

Abstract

As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are [...] Read more.

As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R², Q², and P² for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R² = 0.99, Q² = 0.83 and P² = 0.79 for anti-Tbr activity and R² = 0.94, Q² = 0.64, P² = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure–activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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8 pages, 621 KiB

Open AccessFeature PaperCommunication

Bauerenol Acetate, the Pentacyclic Triterpenoid from Tabernaemontana longipes, is an Antitrypanosomal Agent

by Simira Carothers¹, Rogers Nyamwihura¹, Jasmine Collins¹, Huaisheng Zhang¹, HaJeung Park², William N. Setzer³

and Ifedayo Victor Ogungbe^1,*

¹ Department of Chemistry, Jackson State University, Jackson, MS 39217, USA

² X-ray Crystallography Laboratory, Scripps Research Institute-FL, Jupiter, FL 33458, USA

³ Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA

Molecules 2018, 23(2), 355; https://doi.org/10.3390/molecules23020355 - 8 Feb 2018

Cited by 8 | Viewed by 5140

Abstract

The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory [...] Read more.

The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory activity against Trypanosoma brucei. The active principle in the fraction was isolated, purified, and characterized by NMR and mass spectrometry. The antitrypanosomal agent in the CHCl₃ extract of T. longipes leaves is the pentacyclic triterpenoid bauerenol acetate. A metabolite profiling assay suggest that the triterpenoid influences cholesterol metabolism. The molecular target(s) of bauerenol and its acetate, like many other antiparasitic pentacyclic triterpenoids is/are unknown, but they present privileged structural scaffolds that can be explored for structure-based activity optimization studies using phenotypic assays. Full article

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8 pages, 541 KiB

Open AccessArticle

Sesquiterpene Lactones from Vernonia cinerascens Sch. Bip. and Their in Vitro Antitrypanosomal Activity

by Njogu M. Kimani¹

, Josphat C. Matasyoh², Marcel Kaiser^3,4

, Reto Brun^3,4 and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany

² Department of Chemistry, Egerton University, P.O. Box 536, Egerton 20115, Kenya

³ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, CH-4051 Basel, Switzerland

⁴ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

Molecules 2018, 23(2), 248; https://doi.org/10.3390/molecules23020248 - 27 Jan 2018

Cited by 22 | Viewed by 5152

Abstract

In the endeavor to obtain new antitrypanosomal agents, particularly sesquiterpene lactones, from Kenyan plants of the family Asteraceae, Vernonia cinerascens Sch. Bip. was investigated. Bioactivity-guided fractionation and isolation in conjunction with LC/MS-based dereplication has led to the identification of vernodalol (1) [...] Read more.

In the endeavor to obtain new antitrypanosomal agents, particularly sesquiterpene lactones, from Kenyan plants of the family Asteraceae, Vernonia cinerascens Sch. Bip. was investigated. Bioactivity-guided fractionation and isolation in conjunction with LC/MS-based dereplication has led to the identification of vernodalol (1) and isolation of vernodalin (2), 11β,13-dihydrovernodalin (3), 11β,13-dihydrovernolide (4), vernolide (5), 11β,13-dihydrohydroxyvernolide (6), hydroxyvernolide (7), and a new germacrolide type sesquiterpene lactone vernocinerascolide (8) from the dichloromethane extract of V. cinerascens leaves. Compounds 3–8 were characterized by extensive analysis of their 1D and 2D NMR spectroscopic and HR/MS spectrometric data. All the compounds were evaluated for their in vitro biological activity against bloodstream forms of Trypanosoma brucei rhodesiense and for cytotoxicity against the mammalian cell line L6. Vernodalin (2) was the most active compound with an IC₅₀ value of 0.16 µM and a selectivity index of 35. Its closely related congener 11β,13-dihydrovernodalin (3) registered an IC₅₀ value of 1.1 µM and a selectivity index of 4.2. Full article

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7 pages, 1266 KiB

Open AccessFeature PaperArticle

Arnica Tincture Cures Cutaneous Leishmaniasis in Golden Hamsters

by Sara M. Robledo¹

, Ivan D. Vélez¹ and Thomas J. Schmidt^2,*

¹ PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, 0500100 Medellin, Colombia

² Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus-Corrensstrasse 48, D-48149 Münster, Germany

Molecules 2018, 23(1), 150; https://doi.org/10.3390/molecules23010150 - 12 Jan 2018

Cited by 9 | Viewed by 5651

Abstract

In search for potential therapeutic alternatives to existing treatments for cutaneous Leishmaniasis, we have investigated the effect of Arnica tincture Ph. Eur. (a 70% hydroethanolic tincture prepared from flowerheads of Arnica montana L.) on the lesions caused by infection with Leishmania braziliensis in [...] Read more.

In search for potential therapeutic alternatives to existing treatments for cutaneous Leishmaniasis, we have investigated the effect of Arnica tincture Ph. Eur. (a 70% hydroethanolic tincture prepared from flowerheads of Arnica montana L.) on the lesions caused by infection with Leishmania braziliensis in a model with golden hamsters. The animals were treated topically with a daily single dose of the preparation for 28 days. Subsequently, the healing process was monitored by recording the lesion size in intervals of 15 days up to day 90. As a result, Arnica tincture fully cured three out of five hamsters while one animal showed an improvement and another one suffered from a relapse. This result was slightly better than that obtained with the positive control, meglumine antimonate, which cured two of five hamsters while the other three showed a relapse after 90 days. This result encourages us to further investigate the potential of Arnica tincture in the treatment of cutaneous Leishmaniasis. Full article

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10 pages, 420 KiB

Open AccessArticle

Antimalarial Activity of Acetylenic Thiophenes from Echinops hoehnelii Schweinf

by Helen Bitew^1,2, Wendimagegn Mammo³, Ariaya Hymete¹ and Mariamawit Yonathan Yeshak^1,*

¹ Department of Pharmaceutical Chemistry and Pharmacognosy, School of pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa P.O. Box 9086, Ethiopia

² DDepartment of Pharmacognosy, School of Pharmacy, College of Health Sciences, Mekelle University, P.O.Box 1871, Ethiopia

³ Department of Chemistry, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa P.O. Box 1176, Ethiopia

Molecules 2017, 22(11), 1965; https://doi.org/10.3390/molecules22111965 - 21 Nov 2017

Cited by 13 | Viewed by 5106

Abstract

Malaria is one of the world’s most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds [...] Read more.

Malaria is one of the world’s most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy-but-1-yn)-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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14 pages, 1647 KiB

Open AccessArticle

Baccharis reticularia DC. and Limonene Nanoemulsions: Promising Larvicidal Agents for Aedes aegypti (Diptera: Culicidae) Control

by Gisele Da S. Botas¹

, Rodrigo A. S. Cruz²

, Fernanda B. De Almeida², Jonatas L. Duarte²

, Raquel S. Araújo², Raimundo Nonato P. Souto², Ricardo Ferreira², José Carlos T. Carvalho², Marcelo G. Santos³, Leandro Rocha⁴, Vera Lúcia P. Pereira¹ and Caio P. Fernandes^2,*

¹ Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil

² Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68.903-419, Brazil

³ Faculty of Teacher Training, University of the State of Rio de Janeiro, São Gonçalo 24435-005, Brazil

⁴ Department of Pharmaceutical Technology, Faculty of Pharmacy, Fluminense Federal University, Niterói 24210-346, Brazil

Molecules 2017, 22(11), 1990; https://doi.org/10.3390/molecules22111990 - 17 Nov 2017

Cited by 72 | Viewed by 6864

Abstract

Baccharis reticularia DC. is a plant species from the Asteraceae family that is endemic to Brazil. Despite the great importance of Baccharis genus, no study has been carried out regarding either the phytochemical composition of B. reticularia or the evaluation of its larvicidal [...] Read more.

Baccharis reticularia DC. is a plant species from the Asteraceae family that is endemic to Brazil. Despite the great importance of Baccharis genus, no study has been carried out regarding either the phytochemical composition of B. reticularia or the evaluation of its larvicidal potential. Considering the intrinsic immiscibility of essential oils, this study shows larvicidal nanoemulsions containing the B. reticularia phytochemically characterized essential oil and its main constituent against Aedes aegypti. The major compound found was d-limonene (25.7%). The essential oil inhibited the acetylcholinesterase, one of the main targets of insecticides. The required hydrophile-lipophile balance of both nanoemulsions was 15.0. The mean droplet sizes were around 90.0 nm, and no major alterations were observed after 24 h of preparation for both formulations. After 48 h of treatment, the estimated LC₅₀ values were 118.94 μg mL⁻¹ and 81.19 μg mL⁻¹ for B. reticularia essential oil and d-limonene nanoemulsions, respectively. Morphological alterations evidenced by scanning electron micrography were observed on the larvae treated with the d-limonene nanoemulsion. This paper demonstrated a simple and ecofriendly method for obtaining B. reticularia essential oil and d-limonene aqueous nanoemulsions by a non-heating and solvent-free method, as promising alternatives for Aedes aegypti control. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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9 pages, 667 KiB

Open AccessArticle

Four Prenylflavone Derivatives with Antiplasmodial Activities from the Stem of Tephrosia purpurea subsp. leptostachya

by Yoseph Atilaw¹, Lois Muiva-Mutisya¹, Albert Ndakala¹, Hoseah M. Akala²

, Redemptah Yeda², Yu J. Wu³, Paolo Coghi³, Vincent K. W. Wong³

, Máté Erdélyi^4,5,*

and Abiy Yenesew^1,*

¹ Department of Chemistry, University of Nairobi, Nairobi, P.O. Box 30197-00100, Kenya

² Global Emerging Infections Surveillance (GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)—Walter Reed Project, Kisumu and Nairobi, P.O. Box 54-40100, Kisumu, Kenya

³ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.O. Box 999078, China

⁴ Department of Chemistry and Molecular Biology, University of Gothenburg, SE-40530 Gothenburg, Sweden

⁵ Swedish NMR Centre, University of Gothenburg, P.O. Box 465, SE-40530 Gothenburg, Sweden

Molecules 2017, 22(9), 1514; https://doi.org/10.3390/molecules22091514 - 10 Sep 2017

Cited by 13 | Viewed by 6421

Abstract

Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5–11), were isolated from the [...] Read more.

Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5–11), were isolated from the CH₂Cl₂/MeOH (1:1) extract of the stem of Tephrosia purpurea subsp. leptostachya, a widely used medicinal plant. Their structures were elucidated on the basis of NMR spectroscopic and mass spectrometric evidence. Some of the isolated compounds showed antiplasmodial activity against the chloroquine-sensitive D6 strains of Plasmodium falciparum, with (E)-5-hydroxytephrostachin (1) being the most active, IC₅₀ 1.7 ± 0.1 μM, with relatively low cytotoxicity, IC₅₀ > 21 μM, against four cell-lines. Full article

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13 pages, 1106 KiB

Open AccessArticle

Extracts Obtained from Pterocarpus angolensis DC and Ziziphus mucronata Exhibit Antiplasmodial Activity and Inhibit Heat Shock Protein 70 (Hsp70) Function

by Tawanda Zininga¹, Chinedu P. Anokwuru², Muendi T. Sigidi³, Milingoni P. Tshisikhawe⁴, Isaiah I. D. Ramaite²

, Afsatou N. Traoré³

, Heinrich Hoppe⁵

, Addmore Shonhai^1,* and Natasha Potgieter^3,6

¹ Biochemistry Department, School of Mathematical and Natural Sciences, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa

² Chemistry Department, School of Mathematical and Natural Sciences, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa

³ Microbiology Department, School of Mathematical and Natural Sciences, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa

⁴ Botany Department, School of Mathematical and Natural Sciences, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa

⁵ Department of Biochemistry and Microbiology, Rhodes University, P.O. Box 94, Grahamstown 6140, South Africa

⁶ School of Mathematical and Natural Sciences, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa

Molecules 2017, 22(8), 1224; https://doi.org/10.3390/molecules22081224 - 28 Jul 2017

Cited by 17 | Viewed by 5880

Abstract

Malaria parasites are increasingly becoming resistant to currently used antimalarial therapies, therefore there is an urgent need to expand the arsenal of alternative antimalarial drugs. In addition, it is also important to identify novel antimalarial drug targets. In the current study, extracts of [...] Read more.

Malaria parasites are increasingly becoming resistant to currently used antimalarial therapies, therefore there is an urgent need to expand the arsenal of alternative antimalarial drugs. In addition, it is also important to identify novel antimalarial drug targets. In the current study, extracts of two plants, Pterocarpus angolensis and Ziziphus mucronata were obtained and their antimalarial functions were investigated. Furthermore, we explored the capability of the extracts to inhibit Plasmodium falciparum heat shock protein 70 (Hsp70) function. Heat shock protein 70 (Hsp70) are molecular chaperones whose function is to facilitate protein folding. Plasmodium falciparum the main agent of malaria, expresses two cytosol-localized Hsp70s: PfHsp70-1 and PfHsp70-z. The PfHsp70-z has been reported to be essential for parasite survival, while inhibition of PfHsp70-1 function leads to parasite death. Hence both PfHsp70-1 and PfHsp70-z are potential antimalarial drug targets. Extracts of P. angolensis and Z. mucronata inhibited the basal ATPase and chaperone functions of the two parasite Hsp70s. Furthermore, fractions of P. angolensis and Z. mucronata inhibited P. falciparum 3D7 parasite growth in vitro. The extracts obtained in the current study exhibited antiplasmodial activity as they killed P. falciparum parasites maintained in vitro. In addition, the findings further suggest that some of the compounds in P. angolensis and Z. mucronata may target parasite Hsp70 function. Full article

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13 pages, 722 KiB

Open AccessArticle

Steroid Alkaloids from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense

by Charles Okeke Nnadi^1,2

, Ngozi Justina Nwodo², Marcel Kaiser^3,4

, Reto Brun^3,4 and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany

² Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria Nsukka, Enugu State 410001, Nigeria

³ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, CH-4051 Basel, Switzerland

⁴ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

Molecules 2017, 22(7), 1129; https://doi.org/10.3390/molecules22071129 - 6 Jul 2017

Cited by 36 | Viewed by 7638

Abstract

In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, “sleeping sickness”), we have investigated extracts from the leaves and bark of the West African Holarrhena africana (syn. Holarrhena floribunda; Apocynaceae). The [...] Read more.

In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, “sleeping sickness”), we have investigated extracts from the leaves and bark of the West African Holarrhena africana (syn. Holarrhena floribunda; Apocynaceae). The extracts and their alkaloid-enriched fractions displayed promising in vitro activity against bloodstream forms of T. brucei rhodesiense (Tbr; East African HAT). Bioactivity-guided chromatographic fractionation of the alkaloid-rich fractions resulted in the isolation of 17 steroid alkaloids, one nitrogen-free steroid and one alkaloid-like non-steroid. Impressive activities (IC₅₀ in µM) against Tbr were recorded for 3β-holaphyllamine (0.40 ± 0.28), 3α-holaphyllamine (0.37 ± 0.16), 3β-dihydroholaphyllamine (0.67 ± 0.03), N-methylholaphyllamine (0.08 ± 0.01), conessimine (0.17 ± 0.08), conessine (0.42 ± 0.09), isoconessimine (0.17 ± 0.11) and holarrhesine (0.12 ± 0.08) with selectivity indices ranging from 13 to 302. Based on comparison of the structures of this congeneric series of steroid alkaloids and their activities, structure-activity relationships (SARs) could be established. It was found that a basic amino group at position C-3 of the pregnane or pregn-5-ene steroid nucleus is required for a significant anti-trypanosomal activity. The mono-methylated amino group at C-3 represents an optimum for activity. ∆^5,6 unsaturation slightly increased the activity while hydrolysis of C-12β ester derivatives led to a loss of activity. An additional amino group at C-20 engaged in a pyrrolidine ring closed towards C-18 significantly increased the selectivity index of the compounds. Our findings provide useful empirical data for further development of steroid alkaloids as a novel class of anti-trypanosomal compounds which represent a promising starting point towards new drugs to combat human African trypanosomiasis. Full article

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10 pages, 1770 KiB

Open AccessArticle

Leishmanicidal Activity and Structure-Activity Relationships of Essential Oil Constituents

by Audrey R. S. T. Silva¹, Ricardo Scher², Flaviane V. Santos², Sebastião R. Ferreira^3,4, Sócrates C. H. Cavalcanti¹, Cristiane B. Correa², Lilian L. Bueno³, Ricardo J. Alves⁵, Damião P. Souza⁶

, Ricardo T. Fujiwara³ and Silvio S. Dolabella^1,7,*

¹ Department of Pharmacy, Federal University of Sergipe, 49100-000 São Cristóvão, Sergipe, Brazil

² Laboratory of Molecular Biology of Pathogenic Bioagents, Department of Morphology, Federal University of Sergipe, 49100-000 São Cristóvão, Sergipe, Brazil

³ Department of Parasitology, Biological Sciences Institute, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil

⁴ Health Science Center, Federal University of Roraima, Av. Cap. Ene Garcez, 69310-000 Boa Vista, Roraima, Brazil

⁵ Department of Pharmaceutical Products, Federal University of Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil

⁶ Department of Pharmaceutical Sciences, Federal University of Paraíba, 58051-900 João Pessoa, Paraíba, Brazil

⁷ Laboratory of Parasitology and Tropical Entomology, Department of Morphology, Federal University of Sergipe, 49100-000 São Cristóvão, Sergipe, Brazil

Molecules 2017, 22(5), 815; https://doi.org/10.3390/molecules22050815 - 16 May 2017

Cited by 43 | Viewed by 6118

Abstract

Several constituents of essential oils have been shown to be active against pathogens such as bacteria, fungi, and protozoa. This study demonstrated the in vitro action of ten compounds present in essential oils against Leishmania amazonensis promastigotes. With the exception of p-cymene, [...] Read more.

Several constituents of essential oils have been shown to be active against pathogens such as bacteria, fungi, and protozoa. This study demonstrated the in vitro action of ten compounds present in essential oils against Leishmania amazonensis promastigotes. With the exception of p-cymene, all evaluated compounds presented leishmanicidal activity, exhibiting IC₅₀ between 25.4 and 568.1 μg mL⁻¹. Compounds with the best leishmanicidal activity presented a phenolic moiety (IC₅₀ between 25.4 and 82.9 μg mL⁻¹). Alicyclic alcohols ((−)-menthol and isoborneol) and ketones ((−)-carvone) promoted similar activity against the parasite (IC₅₀ between 190.2 and 198.9 μg mL⁻¹). Most of the compounds showed low cytotoxicity in L929 fibroblasts. Analysis of the structure-activity relationship of these compounds showed the importance of the phenolic structure for the biological action against the promastigote forms of the parasite. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

9 pages, 546 KiB

Open AccessArticle

Alkamides from Anacyclus pyrethrum L. and Their in Vitro Antiprotozoal Activity

by Julia B. Althaus^1,†, Claudine Malyszek^1,†, Marcel Kaiser^2,3, Reto Brun^2,3 and Thomas J. Schmidt^1,*

¹ Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Corrensstraße 48, Münster D-48149, Germany

² Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, Basel CH-4002, Switzerland

³ University of Basel, Petersplatz 1, Basel CH-4003, Switzerland

^† Part of doctoral thesis of J.B.A. and MSc thesis of C.M.

Molecules 2017, 22(5), 796; https://doi.org/10.3390/molecules22050796 - 12 May 2017

Cited by 23 | Viewed by 6349

Abstract

In our ongoing study to evaluate the antiprotozoal activity of alkamides from Asteraceae, a dichloromethane extract from the roots of Anacyclus pyrethrum L. showed a moderate in vitro activity against the NF54 strain of Plasmodium falciparum and against Leishmania donovani (amastigotes, MHOM/ET/67/L82 strain). [...] Read more.

In our ongoing study to evaluate the antiprotozoal activity of alkamides from Asteraceae, a dichloromethane extract from the roots of Anacyclus pyrethrum L. showed a moderate in vitro activity against the NF54 strain of Plasmodium falciparum and against Leishmania donovani (amastigotes, MHOM/ET/67/L82 strain). Seven pure alkamides and a mixture of two further alkamides were isolated by column chromatography followed by preparative high performance liquid chromatography. The alkamides were identified by mass- and NMR-spectroscopic methods as tetradeca-2E,4E-dien-8,10-diynoic acid isobutylamide (anacycline, 1), deca-2E,4E-dienoic acid isobutylamide (pellitorine, 2), deca-2E,4E,9-trienoic acid isobutylamide (3), deca-2E,4E-dienoic acid 2-phenylethylamide (4), undeca-2E,4E-dien-8,10-diynoic acid isopentylamide (5), tetradeca-2E,4E,12Z-trien-8,10-diynoic acid isobutylamide (6), and dodeca-2E,4E-dien acid 4-hydroxy-2-phenylethylamide (7). Two compounds—undeca-2E,4E-dien-8,10-diynoic acid 2-phenylethylamide (8) and deca-2E,4E-dienoic acid 4-hydroxy-2-phenylethylamide (9)—were isolated as an inseparable mixture (1:4). Compounds 3, 4, and 5 were isolated from Anacyclus pyrethrum L. for the first time. While compounds 4 and 5 were previously known from the genus Achillea, compound 3 is a new natural product, to the best of our knowledge. All isolated alkamides were tested in vitro for antiprotozoal activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani and for cytotoxicity against L6 rat skeletal myoblasts. Full article

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19 pages, 828 KiB

Open AccessArticle

Anti-Onchocerca and Anti-Caenorhabditis Activity of a Hydro-Alcoholic Extract from the Fruits of Acacia nilotica and Some Proanthocyanidin Derivatives

by Jacqueline Dikti Vildina¹, Justin Kalmobe¹, Boursou Djafsia¹, Thomas J. Schmidt²

, Eva Liebau³ and Dieudonne Ndjonka^1,*

¹ Department of Biological Sciences, Faculty of Science, University of Ngaoundere, P.O. Box 454, Ngaoundere, Cameroon

² Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Correnstrasse 48, D-48149 Münster, Germany

³ Institute for Zoophysiology, University of Münster, Schlossplatz 8, D-48143 Münster, Germany

Molecules 2017, 22(5), 748; https://doi.org/10.3390/molecules22050748 - 6 May 2017

Cited by 27 | Viewed by 6107

Abstract

Acacia nilotica fruits with high tannin content are used in the northern parts of Cameroon as anti-filarial remedies by traditional healers. In this study, the hydro-alcoholic fruit extract (crude extract (CE)) and, one of the main constituents in its most active fractions, (+)-catechin-3- [...] Read more.

Acacia nilotica fruits with high tannin content are used in the northern parts of Cameroon as anti-filarial remedies by traditional healers. In this study, the hydro-alcoholic fruit extract (crude extract (CE)) and, one of the main constituents in its most active fractions, (+)-catechin-3-O-gallate (CG), as well as four related proanthocyanidins, (−)-epicatechin-3-O-gallate (ECG), (+)-gallocatechin (GC), (−)-epigallocatechin (EGC) and (−)-epigallocatechin-3-O-gallate (EGCG), were assessed for their potential in vitro anthelmintic properties against the free-living model organism Caenorhabditis elegans and against the cattle filarial parasite Onchocerca ochengi. Worms were incubated in the presence of different concentrations of fruit extract, fractions and pure compounds. The effects on mortality were monitored after 48 h. The plant extract and all of the pure tested compounds were active against O. ochengi (LC₅₀ ranging from 1.2 to 11.5 µg/mL on males) and C. elegans (LC₅₀ ranging from 33.8 to 350 µg/mL on wild type). While high LC₅₀ were required for the effects of the compounds on C. elegans, very low LC₅₀ were required against O. ochengi. Importantly, tests for acute oral toxicity (lowest dose: 10 mg/kg) in Wistar rats demonstrated that crude extract and pure compounds were non-toxic and safe to use. Additionally, the results of cytotoxicity tests with the Caco-2 cell line (CC₅₀ ranging from 47.1 to 93.2 µg/mL) confirmed the absence of significant toxicity of the crude extract and pure compounds. These results are in good accordance with the use of A. nilotica against nematode infections by traditional healers, herdsmen and pastoralists in Cameroon. Full article

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12 pages, 2557 KiB

Open AccessArticle

Investigation of the Anti-Leishmania (Leishmania) infantum Activity of Some Natural Sesquiterpene Lactones

by Imke F. Wulsten¹, Thais A. Costa-Silva², Juliana T. Mesquita², Marta L. Lima^2,3, Mariana K. Galuppo², Noemi N. Taniwaki², Samanta E. T. Borborema², Fernando B. Da Costa⁴

, Thomas J. Schmidt^5,*

and Andre G. Tempone^2,*

¹ Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany

² Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 São Paulo, SP, Brazil

³ Instituto de Medicina Tropical, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 470, CEP 05403-000 São Paulo, SP, Brazil

⁴ AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeirão Preto, USP, Av. do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil

⁵ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstraße 48, 48149 Münster, Germany

Molecules 2017, 22(5), 685; https://doi.org/10.3390/molecules22050685 - 25 Apr 2017

Cited by 23 | Viewed by 7180

Abstract

Leishmaniases are neglected infectious diseases caused by parasites of the ‘protozoan’ genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the [...] Read more.

Leishmaniases are neglected infectious diseases caused by parasites of the ‘protozoan’ genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the search for new anti-leishmanial hit compounds, seven natural sesquiterpene lactones were evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum, a pathogen causing VL. The pseudoguaianolides mexicanin I and helenalin acetate demonstrated the highest selectivity and potency against intracellular amastigotes. In addition, promastigotes treated with helenalin acetate were subject to an ultrastructural and biochemical investigation. The lethal action of the compound was investigated by fluorescence-activated cell sorting and related techniques to detect alterations in reactive oxygen species (ROS) content, plasma membrane permeability, and mitochondrial membrane potential. Helenalin acetate significantly reduced the mitochondrial membrane potential and the mitochondrial structural damage was also confirmed by transmission electron microscopy, displaying an intense organelle swelling. No alteration of plasma membrane permeability or ROS content could be detected. Additionally, helenalin acetate significantly increased the production of nitric oxide in peritoneal macrophages, probably potentiating the activity against the intracellular amastigotes. Helenalin acetate could hence be a useful anti-leishmanial scaffold for further optimization studies. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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20 pages, 2720 KiB

Open AccessReview

Potential Antivirals: Natural Products Targeting Replication Enzymes of Dengue and Chikungunya Viruses

by Ana Flávia Costa da Silveira Oliveira^1,2, Róbson Ricardo Teixeira^3,*

, André Silva de Oliveira^1,2, Ana Paula Martins de Souza³, Milene Lopes da Silva³ and Sérgio Oliveira de Paula^1,*

¹ Departamento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, 36570-900 Viçosa, MG, Brazil

² Instituto Federal de Educação, Ciência e Tecnologia do Norte de Minas, 39900-000 Almenara, MG, Brazil

³ Departamento de Química, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, 36570-900 Viçosa, MG, Brazil

Molecules 2017, 22(3), 505; https://doi.org/10.3390/molecules22030505 - 22 Mar 2017

Cited by 65 | Viewed by 11079

Abstract

Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations [...] Read more.

Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations were conducted over the past few years to find antiviral compounds for the treatment of DENV and CHIKV infections. One attractive strategy is the screening of compounds that target enzymes involved in the replication of both DENV and CHIKV. In this review, we describe advances in the evaluation of natural products targeting the enzymes involved in the replication of these viruses. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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19 pages, 1876 KiB

Open AccessReview

Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

by Chonny Herrera Acevedo, Luciana Scotti

, Mateus Feitosa Alves, Margareth De Fátima Formiga Melo Diniz and Marcus Tullius Scotti^*

Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil

Molecules 2017, 22(1), 79; https://doi.org/10.3390/molecules22010079 - 3 Jan 2017

Cited by 35 | Viewed by 9493

Abstract

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, [...] Read more.

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 543 KiB

Open AccessArticle

Evaluation of Chemical Composition and Antileishmanial and Antituberculosis Activities of Essential Oils of Piper Species

by Karine Zanoli Bernuci¹, Camila Cristina Iwanaga¹, Carla Maria Mariano Fernandez-Andrade¹, Fabiana Brusco Lorenzetti¹, Eduardo Caio Torres-Santos²

, Viviane Dos Santos Faiões², José Eduardo Gonçalves^3,4

, Wanderlei Do Amaral⁵, Cícero Deschamps⁵, Regiane Bertin de Lima Scodro⁶, Rosilene Fressatti Cardoso⁶, Vanessa Pietrowski Baldin⁶ and Diógenes Aparício Garcia Cortez^1,4,*

¹ Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá 87020-900, PR, Brazil

² Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-900, RJ, Brazil

³ Mestrado em Tecnologias Limpas e Mestrado em Promoção da Saúde, UniCesumar, Av. Guerdner, 1610, Jd. Aclimação, Maringá 87050-390, PR, Brazil

⁴ Instituto Cesumar de Ciências, Tecnologia e Inovação—ICETI, Av. Guerdner, 1610, Jd. Aclimação, Maringá 87050-390, PR, Brazil

⁵ Setor de Ciências Agrárias/Departamento de Fitotecnia e Fitossanitaríssimo, Universidade Federal do Paraná, Curitiba 88035-050, PR, Brazil

⁶ Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá 87020-900, PR, Brazil

Molecules 2016, 21(12), 1698; https://doi.org/10.3390/molecules21121698 - 12 Dec 2016

Cited by 59 | Viewed by 7874

Abstract

Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC–MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority [...] Read more.

Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC–MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority of species analyzed. The composition of the essential oil of Piper mosenii was described for the first time. The cytotoxicity of the essential oils was evaluated in peritoneal macrophages and the oils of P. rivinoides, P. arboretum, and P. aduncum exhibited the highest values, with cytotoxic concentration at 50% (CC₅₀) > 200 µg/mL. Both P. diospyrifolium and P. aduncum displayed activity against Leishmania amazonensis, and were more selective for the parasite than for the macrophages, with a selectivity index (SI) of 2.35 and >5.52, respectively. These SI values were greater than the 1 for the standard drug pentamidine. The antileishmanial activity of the essential oils of P. diospyrifolium and P. aduncum was described for the first time. P. rivinoides, P. cernuum, and P. diospyrifolium displayed moderate activity against the Mycobacterium tuberculosis H₃₇Rv bacillus, with a minimum inhibitory concentration (MIC) of 125 µg/mL. These results are relevant and suggests their potential for therapeutic purposes. Nevertheless, further studies are required to explain the exact mechanism of action of these essential oils. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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48 pages, 5610 KiB

Open AccessReview

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

by Ifedayo Victor Ogungbe¹

and William N. Setzer^2,*

¹ Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, USA

² Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA

Molecules 2016, 21(10), 1389; https://doi.org/10.3390/molecules21101389 - 19 Oct 2016

Cited by 38 | Viewed by 13171

Abstract

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a [...] Read more.

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 407 KiB

Open AccessArticle

Antiprotozoal and Antiglycation Activities of Sesquiterpene Coumarins from Ferula narthex Exudate

by Adnan Amin¹, Emmy Tuenter¹, Paul Cos²

, Louis Maes²

, Vassiliki Exarchou¹, Sandra Apers¹ and Luc Pieters^1,*

¹ Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium

² Laboratory of Parasitology, Microbiology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium

Molecules 2016, 21(10), 1287; https://doi.org/10.3390/molecules21101287 - 26 Sep 2016

Cited by 33 | Viewed by 6226

Abstract

The exudate of Ferula narthex Boiss. (Apiaceae) is widely used in the Indian subcontinent as a spice and because of its health effects. Six sesquiterpene coumarins have been isolated from this exudate: feselol, ligupersin A, asacoumarin A, 8′-O-acetyl-asacoumarin A, 10′R [...] Read more.

The exudate of Ferula narthex Boiss. (Apiaceae) is widely used in the Indian subcontinent as a spice and because of its health effects. Six sesquiterpene coumarins have been isolated from this exudate: feselol, ligupersin A, asacoumarin A, 8′-O-acetyl-asacoumarin A, 10′R-karatavacinol and 10′R-acetyl-karatavacinol. Based on its use in infectious and diabetic conditions, the isolated constituents were evaluated for antimicrobial and antiglycation activities. Some compounds showed activity against protozoal parasites, asacoumarin A being the most active one against Plasmodium falciparum K1 (IC₅₀ 1.3 μM). With regard to antiglycation activity, in the BSA-glucose test, ligupersin A displayed the highest activity (IC₅₀ 0.41 mM), being more active than the positive control aminiguanidine (IC₅₀ 1.75 mM). In the BSA-MGO assay, the highest activity was shown by 8′-O-acetyl-asacoumarin A (IC₅₀ 1.03 mM), being less active than aminoguanidine (IC₅₀ 0.15 mM). Hence, the antiglycation activity of the isolated constituents was due to both oxidative and non-oxidative modes of inhibition. Full article

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14 pages, 1134 KiB

Open AccessArticle

ent-Pimarane and ent-Kaurane Diterpenes from Aldama discolor (Asteraceae) and Their Antiprotozoal Activity

by Mauro S. Nogueira¹, Fernando B. Da Costa²

, Reto Brun^3,4, Marcel Kaiser^3,4 and Thomas J. Schmidt^1,*

¹ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, Münster D-48149, Germany

² AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeirão Preto, USP, Av. do Café s/n, Ribeirão Preto-SP 14040-903, Brazil

³ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, Basel CH-4051, Switzerland

⁴ University of Basel, Petersplatz 1, Basel CH-4003, Switzerland

Molecules 2016, 21(9), 1237; https://doi.org/10.3390/molecules21091237 - 15 Sep 2016

Cited by 26 | Viewed by 7112

Abstract

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian “Cerrado”, which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to [...] Read more.

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian “Cerrado”, which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. In this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1), as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2), ent-2S,4S-2-19-epoxy-pimara-8(3),15-diene-7β-ol (3) and ent-7-oxo-pimara-8,15-diene-3β-ol (4), were isolated from the dichloromethane extract of A. discolor leaves and identified by means of MS and NMR. The compounds were assayed in vitro against Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, Plasmodium falciparum and also tested for cytotoxicity against mammalian cells (L6 cell line). The ent-kaurane 1 showed significant in vitro activity against both P. falciparum (IC

_{50}

= 3.5

μ

M) and L. donovani (IC

_{50}

= 2.5

μ

M) and ent-pimarane 2 against P. falciparum (IC

_{50}

= 3.8

μ

M). Both compounds returned high selectivity indices (SI >10) in comparison with L6 cells, which makes them interesting candidates for in vivo tests. In addition to the diterpenes, the sesquiterpene lactone budlein A (5), which has been reported to possess a strong anti-T. b. rhodesiense activity, was identified as major compound in the A. discolor extract and explains its high activity against this parasite (100% growth inhibition at 2

μ

g/mL). Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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13 pages, 906 KiB

Open AccessArticle

Antidiarrheal Thymol Derivatives from Ageratina glabrata. Structure and Absolute Configuration of 10-Benzoyloxy-8,9-epoxy-6-hydroxythymol Isobutyrate

by Celia Bustos-Brito^1,*

, Valeria J. Vázquez-Heredia¹, Fernando Calzada², Lilian Yépez-Mulia³, José S. Calderón¹, Simón Hernández-Ortega¹, Baldomero Esquivel¹, Normand García-Hernández⁴

and Leovigildo Quijano^1,*

¹ Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, D.F. 04510, Mexico

² UIM en Farmacología, 2o Piso CORCE, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, México, D.F. 06725, Mexico

³ UIM en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, México, D.F. 06725, Mexico

⁴ UIM en Genética Humana, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, México, D.F. 06725, Mexico

Molecules 2016, 21(9), 1132; https://doi.org/10.3390/molecules21091132 - 12 Sep 2016

Cited by 14 | Viewed by 6507

Abstract

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with [...] Read more.

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with other two already known thymol derivatives identified as 10-benzoyloxy-8,9-epoxy-6-methoxythymol isobutyrate (2) and 10-benzoyloxy-8,9-epoxythymol isobutyrate (3) were also obtained. In this paper, we report the structures and complete assignments of the ¹H and ¹³C-NMR data of compounds 1–7, and the absolute configuration for compound 1, unambiguously established by single crystal X-ray diffraction, and evaluation of the Flack parameter. The in vitro antiprotozoal assay showed that compound 1 and its derivative 1a were the most potent antiamoebic and antigiardial compounds. Both compounds showed selectivity and good antiamoebic activity comparable to emetine and metronidazole, respectively, two antiprotozoal drugs used as positive controls. In relation to anti-propulsive effect, compound 1 and 1a showed inhibitory activity, with activities comparable to quercetin and compound 9, two natural antipropulsive compounds used as positive controls. These data suggest that compound 1 may play an important role in antidiarrheal properties of Ageratina glabrata. Full article

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10 pages, 387 KiB

Open AccessCommunication

In Vitro Antileishmanial Activity of Sterols from Trametes versicolor (Bres. Rivarden)

by Vivian Leliebre-Lara^1,*

, Lianet Monzote Fidalgo², Eva-Maria Pferschy-Wenzig³, Olaf Kunert⁴, Clara Nogueiras Lima¹ and Rudolf Bauer³

¹ Centre for Natural Product Studies, Faculty of Chemistry, University of Havana, Zapata y G, La Habana 10400, Cuba

² Parasitology Department, Institute of Tropical Medicine “Pedro Kouri” Marianao 13, Havana 10400, Cuba

³ Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitaetsplatz 4, 8010 Graz, Austria

⁴ Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Universitaetsplatz 4, 8010 Graz, Austria

Molecules 2016, 21(8), 1045; https://doi.org/10.3390/molecules21081045 - 10 Aug 2016

Cited by 33 | Viewed by 6811

Abstract

Two ergostanes, 5α,8α-epidioxy-22E-ergosta-6,22-dien-3β-ol (1) and 5α-ergost-7,22-dien-3β-ol (2), and a lanostane, 3β-hydroxylanostan-8,24-diene-21-oic acid (trametenolic acid) (3), were isolated from an n-hexane extract prepared from the fruiting body of Trametes versicolor (Bres. Rivarden). The activity of [...] Read more.

Two ergostanes, 5α,8α-epidioxy-22E-ergosta-6,22-dien-3β-ol (1) and 5α-ergost-7,22-dien-3β-ol (2), and a lanostane, 3β-hydroxylanostan-8,24-diene-21-oic acid (trametenolic acid) (3), were isolated from an n-hexane extract prepared from the fruiting body of Trametes versicolor (Bres. Rivarden). The activity of the isolated sterols was evaluated against promastigotes and amastigotes of Leishmania amazonensis Lainson and Shaw, 1972. The lanostane, compound (3), showed the best inhibitory response (IC₅₀ promastigotes 2.9 ± 0.1 μM and IC₅₀ amastigotes 1.6 ± 0.1 μM). This effect was 25-fold higher compared with its cytotoxic effect on peritoneal macrophages from BALB/c mice. Therefore, trametenolic acid could be regarded as a promising lead for the synthesis of compounds with antileishmanial activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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19 pages, 4868 KiB

Open AccessArticle

In Vitro Reversible and Time-Dependent CYP450 Inhibition Profiles of Medicinal Herbal Plant Extracts Newbouldia laevis and Cassia abbreviata: Implications for Herb-Drug Interactions

by Nicholas Ekow Thomford^1,2

, Kevin Dzobo^3,4

, Denis Chopera⁵, Ambroise Wonkam¹, Alfred Maroyi⁶

, Dee Blackhurst⁷

and Collet Dandara^1,*

¹ Division of Human Genetics, Department of Pathology & Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa

² School of Medical Sciences, University of Cape Coast, Cape Coast, PMB, Ghana

³ ICGEB, Cape Town Component, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa

⁴ Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa

⁵ Division of Medical Virology, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa

⁶ Department of Botany, University of Fort Hare, Private Bag X1314, Alice 5700, South Africa

⁷ Division of Chemical Pathology, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa

Molecules 2016, 21(7), 891; https://doi.org/10.3390/molecules21070891 - 7 Jul 2016

Cited by 35 | Viewed by 9067

Abstract

This study evaluated the effects of Newbouldia laevis and Cassia abbreviata extracts on CYP450 enzyme activity. Recombinant CYP450 enzyme and fluorogenic substrates were used for evaluating inhibition, allowing the assessment of herb–drug interactions (HDI). Phytochemical fingerprinting was performed using UPLC-MS. The herbal extracts [...] Read more.

This study evaluated the effects of Newbouldia laevis and Cassia abbreviata extracts on CYP450 enzyme activity. Recombinant CYP450 enzyme and fluorogenic substrates were used for evaluating inhibition, allowing the assessment of herb–drug interactions (HDI). Phytochemical fingerprinting was performed using UPLC-MS. The herbal extracts were risk ranked for HDI based on the IC₅₀ values determined for each CYP enzyme. Newbouldia laevis inhibited CYP1A2, CYP2C9, and CYP2C19 enzyme activities with K_i of 2.84 µg/mL, 1.55 µg/mL, and 1.23 µg/mL, respectively. N. laevis exhibited a TDI (4.17) effect on CYP1A2 but not CYP2C9 and CYP2C19 enzyme activities. Cassia abbreviata inhibited CYP1A2, CYP2C9, and CYP2C19 enzyme activities showing a K_i of 4.86 µg/mL, 5.98 µg/mL, and 1.58 µg/mL, respectively. TDI potency assessment for Cassia abbreviata showed it as a potential TDI candidate (1.64) for CYP1A2 and CYP2C19 (1.72). UPLC-MS analysis showed that Newbouldia laevis and Cassia abbreviata possess polyphenols that likely give them their therapeutic properties; some of them are likely to be responsible for the observed inhibition. The observations made in this study suggest the potential for these herbal compounds to interact, especially when co-administered with other medications metabolized by these CYP450 enzymes. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 1141 KiB

Open AccessFeature PaperArticle

A New Alkamide with an Endoperoxide Structure from Acmella ciliata (Asteraceae) and Its in Vitro Antiplasmodial Activity

by Narjara Silveira¹, Julia Saar^1,2, Alan Diego C. Santos³, Andersson Barison³, Louis P. Sandjo¹, Marcel Kaiser^4,5, Thomas J. Schmidt^2,*

and Maique W. Biavatti^1,*

¹ Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Bloco J/K, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil

² Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Corrensstraße 48, Münster D-48149, Germany

³ Departamento de Química, Universidade Federal do Paraná, Curitiba 81530-900, PR, Brazil

⁴ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, Basel CH-4051, Switzerland

⁵ University of Basel, Petersplatz 1, Basel CH-4003, Switzerland

Molecules 2016, 21(6), 765; https://doi.org/10.3390/molecules21060765 - 11 Jun 2016

Cited by 22 | Viewed by 8291

Abstract

From the aerial parts of Acmella ciliata (H.B.K.) Cassini (basionym Spilanthes ciliata Kunth; Asteraceae), three alkamides were isolated and identified by mass- and NMR spectroscopic methods as (2E,6E,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), N-(2-phenethyl)-2E [...] Read more.

From the aerial parts of Acmella ciliata (H.B.K.) Cassini (basionym Spilanthes ciliata Kunth; Asteraceae), three alkamides were isolated and identified by mass- and NMR spectroscopic methods as (2E,6E,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), N-(2-phenethyl)-2E-en-6,8-nonadiynamide (2) and (2E,7Z)-6,9-endoperoxy-N-isobutyl-2,7-decadienamide (3). While 1 and 2 are known alkamides, compound 3 has not been described until now. It was found that the unusual cyclic peroxide 3 exists as a racemate of both enantiomers of each alkamide; the 6,9-cis- as well as the 6,9-trans-configured diastereomers, the former represents the major, the latter the minor constituent of the mixture. In vitro tests for activity against the human pathogenic parasites Trypanosoma brucei rhodesiense and Plasmodium falciparum revealed that 1 and 3 possess activity against the NF54 strain of the latter (IC₅₀ values of 4.5 and 5.1 µM, respectively) while 2 was almost inactive. Compound 3 was also tested against multiresistant P. falciparum K1 and was found to be even more active against this parasite strain (IC₅₀ = 2.1 µM) with considerable selectivity (IC₅₀ against L6 rat skeletal myoblasts = 168 µM). Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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13 pages, 224 KiB

Open AccessArticle

In Vitro Activity of Selected West African Medicinal Plants against Mycobacterium ulcerans Disease

by Patrick Valere Tsouh Fokou^1,2,*

, Abena Adomah Kissi-Twum¹, Dorothy Yeboah-Manu³

, Regina Appiah-Opong¹, Phyllis Addo⁴, Lauve Rachel Tchokouaha Yamthe^2,5, Alvine Ngoutane Mfopa², Fabrice Fekam Boyom²

and Alexander Kwadwo Nyarko^1,6

¹ Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra LG 581, Ghana

² Antimicrobial Agents Unit, LPMPS, Department of Biochemistry, Faculty of Science, University of Yaoundé 1, Yaoundé 812, Cameroon

³ Department of Bacteriology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra LG 581, Ghana

⁴ Department of Animal Experimentation, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra LG 581, Ghana

⁵ Institute of Medical Research and Medicinal Plants Studies (IMPM), Yaoundé 6163, Cameroon

⁶ Department of Pharmacology and Toxicology, School of Pharmacy, University of Ghana, Accra LG 43, Ghana

Molecules 2016, 21(4), 445; https://doi.org/10.3390/molecules21040445 - 13 Apr 2016

Cited by 17 | Viewed by 7284

Abstract

Buruli ulcer (BU) is the third most prevalent mycobacteriosis, after tuberculosis and leprosy. The currently recommended combination of rifampicin-streptomycin suffers from side effects and poor compliance, which leads to reliance on local herbal remedies. The objective of this study was to investigate the [...] Read more.

Buruli ulcer (BU) is the third most prevalent mycobacteriosis, after tuberculosis and leprosy. The currently recommended combination of rifampicin-streptomycin suffers from side effects and poor compliance, which leads to reliance on local herbal remedies. The objective of this study was to investigate the antimycobacterial properties and toxicity of selected medicinal plants. Sixty-five extracts from 27 plant species were screened against Mycobacterium ulcerans and Mycobacterium smegmatis, using the Resazurin Microtiter Assay (REMA). The cytotoxicity of promising extracts was assayed on normal Chang liver cells by an MTT assay. Twenty five extracts showed activity with minimal inhibitory concentration (MIC) values ranging from 16 µg/mL to 250 µg/mL against M. smegmatis, while 17 showed activity against M. ulcerans with MIC values ranging from 125 µg/mL to 250 µg/mL. In most of the cases, plant extracts with antimycobacterial activity showed no cytotoxicity on normal human liver cells. Exception were Carica papaya, Cleistopholis patens, and Polyalthia suaveolens with 50% cell cytotoxic concentrations (CC₅₀) ranging from 3.8 to 223 µg/mL. These preliminary results support the use of some West African plants in the treatment of Buruli ulcer. Meanwhile, further studies are required to isolate and characterize the active ingredients in the extracts. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 1299 KiB

Open AccessArticle

Phenolic Constituents of Medicinal Plants with Activity against Trypanosoma brucei

by Ya Nan Sun^1,†, Joo Hwan No^2,†, Ga Young Lee¹

, Wei Li³, Seo Young Yang¹, Gyongseon Yang², Thomas J. Schmidt^4,*

, Jong Seong Kang^1,* and Young Ho Kim^1,*

¹ College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea

² Leishmania Research Laboratory, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi 463-400, Korea

³ School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea

⁴ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstrasse 48, D-48149 Münster, Germany

^† These authors contributed equally to this work.

Molecules 2016, 21(4), 480; https://doi.org/10.3390/molecules21040480 - 12 Apr 2016

Cited by 19 | Viewed by 6912

Abstract

Neglected tropical diseases (NTDs) affect over one billion people all over the world. These diseases are classified as neglected because they impact populations in areas with poor financial conditions and hence do not attract sufficient research investment. Human African Trypanosomiasis (HAT or sleeping [...] Read more.

Neglected tropical diseases (NTDs) affect over one billion people all over the world. These diseases are classified as neglected because they impact populations in areas with poor financial conditions and hence do not attract sufficient research investment. Human African Trypanosomiasis (HAT or sleeping sickness), caused by the parasite Trypanosoma brucei, is one of the NTDs. The current therapeutic interventions for T. brucei infections often have toxic side effects or require hospitalization so that they are not available in the rural environments where HAT occurs. Furthermore, parasite resistance is increasing, so that there is an urgent need to identify novel lead compounds against this infection. Recognizing the wide structural diversity of natural products, we desired to explore and identify novel antitrypanosomal chemotypes from a collection of natural products obtained from plants. In this study, 440 pure compounds from various medicinal plants were tested against T. brucei by in a screening using whole cell in vitro assays. As the result, twenty-two phenolic compounds exhibited potent activity against cultures of T. brucei. Among them, eight compounds—4, 7, 11, 14, 15, 18, 20, and 21—showed inhibitory activity against T. brucei, with IC₅₀ values below 5 µM, ranging from 0.52 to 4.70 μM. Based on these results, we attempt to establish some general trends with respect to structure-activity relationships, which indicate that further investigation and optimization of these derivatives might enable the preparation of potentially useful compounds for treating HAT. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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13 pages, 3628 KiB

Open AccessArticle

Leishmanicidal Activity of (+)-Phyllanthidine and the Phytochemical Profile of Margaritaria nobilis (Phyllanthaceae)

by Lienne S. Moraes^1,2, Marcio R. H. Donza³, Ana Paula D. Rodrigues^2,4, Bruno J. M. Silva^1,2, Davi S. B. Brasil³, Maria Das Graças B. Zoghbi⁵, Eloísa H. A. Andrade^3,5, Giselle M. S. P. Guilhon^3,* and Edilene O. Silva^1,2

¹ Laboratório de Parasitologia e Biologia Estrutural, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará 66075-110, Brazil

² Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil

³ Programa de Pós-Graduação em Química, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, Pará 66075-110, Brazil

⁴ Laboratório de Microscopia Eletrônica, Instituto Evandro Chagas, Secretaria de Vigilância em Saúde, Ministério da Saúde, Belém, Pará 66090-000, Brazil

⁵ Coordenação de Botânica, Museu Paraense Emílio Goeldi, Belém, Pará 66077-901, Brazil

Molecules 2015, 20(12), 22157-22169; https://doi.org/10.3390/molecules201219829 - 11 Dec 2015

Cited by 26 | Viewed by 7805

Abstract

The effects of the Securinega alkaloid (+)-phyllanthidine on Leishmania (L.) amazonensis and the first chemical investigation of Margaritaria nobilis L.f. (Phyllanthaceae) are described. Treating the parasites with this alkaloid caused a dose-dependent reduction in promastigote growth of 67.68% (IC₅₀ 82.37 μg/mL or [...] Read more.

The effects of the Securinega alkaloid (+)-phyllanthidine on Leishmania (L.) amazonensis and the first chemical investigation of Margaritaria nobilis L.f. (Phyllanthaceae) are described. Treating the parasites with this alkaloid caused a dose-dependent reduction in promastigote growth of 67.68% (IC₅₀ 82.37 μg/mL or 353 µM) and in amastigote growth of 83.96% (IC₅₀ 49.11 μg/mL or 210 µM), together with ultrastructural alterations in the promastigotes. No cytotoxic effect was detected in mammalian cells (CC₅₀ 1727.48 µg/mL or CC₅₀ 5268 µM). Classical chromatographic techniques and spectral methods led to the isolation and identification of betulinic acid, kaempferol, corilagin, gallic acid and its methyl ester, besides (+)-phyllanthidine from M. nobilis leaves and stems. Margaritaria nobilis is another source of the small group of Securinega alkaloids, together with other Phyllanthaceae (Euphorbiaceae s.l.) species. The low toxicity to macrophages and the effects against promastigotes and amastigotes are suggestive that (+)-phyllanthidine could be a promising antileishmanial agent for treating cutaneous leishmaniasis. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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1 pages, 601 KiB

Open AccessCorrection

Lewies, A., et al. The Potential Use of Natural and Structural Analogues of Antimicrobial Peptides in the Fight against Neglected Tropical Diseases. Molecules 2015, 20, 15392–15433

by Angélique Lewies, Johannes F. Wentzel, Garmi Jacobs and Lissinda H. Du Plessis^*

Centre of Excellence for Pharmaceutical Sciences (PHARMACEN), North-West University, Potchefstroom 2520, South Africa

Molecules 2015, 20(9), 16757; https://doi.org/10.3390/molecules200916757 - 14 Sep 2015

Cited by 6 | Viewed by 4766

Abstract

The authors wish to make the following corrections to this paper [1]: [...] Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

42 pages, 1661 KiB

Open AccessReview

The Potential Use of Natural and Structural Analogues of Antimicrobial Peptides in the Fight against Neglected Tropical Diseases

by Angélique Lewies, Johannes Frederik Wentzel, Garmi Jacobs and Lissinda Hester Du Plessis^*

Centre of Excellence for Pharmaceutical Sciences (PHARMACEN), North-West University, Potchefstroom 2520, South Africa

Molecules 2015, 20(8), 15392-15433; https://doi.org/10.3390/molecules200815392 - 24 Aug 2015

Cited by 53 | Viewed by 11315 | Correction

Abstract

Recently, research into the development of new antimicrobial agents has been driven by the increase in resistance to traditional antibiotics and Emerging Infectious Diseases. Antimicrobial peptides (AMPs) are promising candidates as alternatives to current antibiotics in the treatment and prevention of microbial infections. [...] Read more.

Recently, research into the development of new antimicrobial agents has been driven by the increase in resistance to traditional antibiotics and Emerging Infectious Diseases. Antimicrobial peptides (AMPs) are promising candidates as alternatives to current antibiotics in the treatment and prevention of microbial infections. AMPs are produced by all known living species, displaying direct antimicrobial killing activity and playing an important role in innate immunity. To date, more than 2000 AMPs have been discovered and many of these exhibit broad-spectrum antibacterial, antiviral and anti-parasitic activity. Neglected tropical diseases (NTDs) are caused by a variety of pathogens and are particularly wide-spread in low-income and developing regions of the world. Alternative, cost effective treatments are desperately needed to effectively battle these medically diverse diseases. AMPs have been shown to be effective against a variety of NTDs, including African trypanosomes, leishmaniosis and Chagas disease, trachoma and leprosy. In this review, the potential of selected AMPs to successfully treat a variety of NTD infections will be critically evaluated. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 552 KiB

Open AccessArticle

Anti-Protozoal Activities of Cembrane-Type Diterpenes from Vietnamese Soft Corals

by Nguyen Phuong Thao^1,2

, Bui Thi Thuy Luyen¹, Reto Brun^3,4, Marcel Kaiser^3,4, Phan Van Kiem², Chau Van Minh², Thomas J. Schmidt^5,*

, Jong Seong Kang^1,* and Young Ho Kim^1,*

¹ College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea

² Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18-Hoang Quoc Viet, Caugiay, Hanoi 10000, Vietnam

³ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, Basel CH-4002, Switzerland

⁴ University of Basel, Petersplatz 1, Basel CH-4003, Switzerland

⁵ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstrasse 48, Münster D-48149, Germany

Molecules 2015, 20(7), 12459-12468; https://doi.org/10.3390/molecules200712459 - 8 Jul 2015

Cited by 29 | Viewed by 7249

Abstract

Based on our previous finding that certain cembranoid diterpenes possess selective toxicity against protozoan pathogens of tropical diseases such as Trypanosoma and Plasmodium, we have subjected a series of 34 cembranes isolated from soft corals living in the Vietnamese sea to an [...] Read more.

Based on our previous finding that certain cembranoid diterpenes possess selective toxicity against protozoan pathogens of tropical diseases such as Trypanosoma and Plasmodium, we have subjected a series of 34 cembranes isolated from soft corals living in the Vietnamese sea to an in vitro screening for anti-protozoal activity against Trypanosoma brucei rhodesiense (Tbr), T. cruzi (Tc), Leishmania donovani (Ld), and Plasmodium falciparum (Pf). Twelve of the tested compounds displayed significant activity against at least one of the parasites. Specifically, 7S,8S-epoxy-1,3,11-cembratriene-16-oic methyl ester (1), (1R,4R,2E,7E,11E)-cembra-2,7,11-trien-4-ol (2), crassumol D (12), crassumol E (13), and (1S,2E,4S,6E,8S,11S)-2,6,12(20)-cembrantriene-4,8,11-triol (16) from Lobophytum crassum, L. laevigatum, and Sinularia maxima showed the highest level of inhibitory activity against T. b. rhodesiense, with IC₅₀ values of about 1 µM or less. Lobocrasol A (6) and lobocrasol C (8) from L. crassum and L. laevigatum exhibited particularly significant inhibitory effects on L. donovani with IC₅₀ values < 0.2 µM. The best antiplasmodial effect was exerted by laevigatol A (10), with an IC₅₀ value of about 3.0 µM. The cytotoxicity of the active compounds on L6 rat skeletal myoblast cell was also assessed and found to be insignificant in all cases. This is the first report on anti-protozoal activity of these compounds, and points out the potential of the soft corals in discovery of new anti-protozoal lead compounds. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 2784 KiB

Open AccessArticle

Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni

by Jan Glaser^1,†, Uta Schurigt^2,*,†, Brian M. Suzuki^3,4, Conor R. Caffrey^3,4 and Ulrike Holzgrabe¹

¹ Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany

² Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2/D15, D-97080 Wuerzburg, Germany

³ Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, 1700 4th St., San Francisco, CA 94158, USA

⁴ Department of Pathology, University of California, San Francisco, CA 94158, USA

^† These authors contributed equally to this work.

Molecules 2015, 20(6), 10873-10883; https://doi.org/10.3390/molecules200610873 - 12 Jun 2015

Cited by 23 | Viewed by 7446

Abstract

Bornyl caffeate (1) was previously isolated by us from Valeriana (V.) wallichii rhizomes and identified as an anti-leishmanial substance. Here, we screened a small compound library of synthesized derivatives 1–30 for activity against schistosomula of Schistosoma (S.) mansoni. [...] Read more.

Bornyl caffeate (1) was previously isolated by us from Valeriana (V.) wallichii rhizomes and identified as an anti-leishmanial substance. Here, we screened a small compound library of synthesized derivatives 1–30 for activity against schistosomula of Schistosoma (S.) mansoni. Compound 1 did not show any anti-schistosomal activity. However, strong phenotypic changes, including the formation of vacuoles, degeneration and death were observed after in vitro treatment with compounds 23 (thymyl cinnamate) and 27 (eugenyl cinnamate). Electron microscopy analysis of the induced vacuoles in the dying parasites suggests that 23 and 27 interfere with autophagy. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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13 pages, 1112 KiB

Open AccessArticle

PLS-Prediction and Confirmation of Hydrojuglone Glucoside as the Antitrypanosomal Constituent of Juglans Spp.

by Therese Ellendorff¹, Reto Brun^2,3, Marcel Kaiser^2,3, Jandirk Sendker^1,† and Thomas J. Schmidt^1,*,†

¹ Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, PharmaCampus, Corrensstr. 48, Münster D-48149, Germany

² Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, Basel CH-4002, Switzerland

³ University of Basel, Petersplatz 1, Basel CH-4003, Switzerland

^† These authors contributed equally to this work.

Molecules 2015, 20(6), 10082-10094; https://doi.org/10.3390/molecules200610082 - 29 May 2015

Cited by 28 | Viewed by 7718

Abstract

Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found [...] Read more.

Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract’s fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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13 pages, 607 KiB

Open AccessArticle

Antitrypanosomal Acetylene Fatty Acid Derivatives from the Seeds of Porcelia macrocarpa (Annonaceae)

by Luciana De Á. Santos^1,*, Alberto J. Cavalheiro¹, Andre G. Tempone², Daniela S. Correa², Tatiana R. Alexandre², Natalia F. Quintiliano³, André F. Rodrigues-Oliveira³, Diogo Oliveira-Silva³, Roberto Carlos C. Martins⁴ and João Henrique G. Lago³

¹ Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais—NuBBE, Instituto de Química, Universidade Estadual Paulista, 14800-060 Araraquara, SP, Brazil

² Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, 01246-902 São Paulo, SP, Brazil

³ Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270 Diadema, SP, Brazil

⁴ Instituto de Pesquisa em Produtos Naturais, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil

Molecules 2015, 20(5), 8168-8180; https://doi.org/10.3390/molecules20058168 - 7 May 2015

Cited by 10 | Viewed by 6909

Abstract

Chagas’ disease is caused by a parasitic protozoan and affects the poorest population in the world, causing high mortality and morbidity. As a result of the toxicity and long duration of current treatments, the discovery of novel and more efficacious drugs is crucial. [...] Read more.

Chagas’ disease is caused by a parasitic protozoan and affects the poorest population in the world, causing high mortality and morbidity. As a result of the toxicity and long duration of current treatments, the discovery of novel and more efficacious drugs is crucial. In this work, the hexane extract from seeds of Porcelia macrocarpa R.E. Fries (Annonaceae) displayed in vitro antitrypanosomal activity against trypomastigote forms of T. cruzi by the colorimetric MTT assay (IC₅₀ of 65.44 μg/mL). Using chromatographic fractionation over SiO₂, this extract afforded a fraction composed by one active compound (IC₅₀ of 10.70 µg/mL), which was chemically characterized as 12,14-octadecadiynoic acid (macrocarpic acid). Additionally, two new inactive acetylene compounds (α,α'-dimacro-carpoyl-β-oleylglycerol and α-macrocarpoyl-α'-oleylglycerol) were also isolated from the hexane extract. The complete characterization of the isolated compounds was performed by analysis of NMR and MS data as well as preparation of derivatives. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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22 pages, 790 KiB

Open AccessReview

Anti-Trypanosomal Activity of Nigerian Plants and Their Constituents

by Ngozi Justina Nwodo^1,*, Akachukwu Ibezim¹, Fidele Ntie-Kang²

, Michael Umale Adikwu³ and Chika John Mbah¹

¹ Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka 410001, Nigeria

² Department of Chemistry, Chemical and Bioactivity Information Centre, Faculty of Science, University of Buea, P.O. Box 63, Buea 00237, Cameroon

³ Department of Pharmaceutics, University of Nigeria, Nsukka 410001, Nigeria

Molecules 2015, 20(5), 7750-7771; https://doi.org/10.3390/molecules20057750 - 28 Apr 2015

Cited by 56 | Viewed by 12063

Abstract

African trypanosomiasis is a vector-borne parasitic disease causing serious risks to the lives of about 60 million people and 48 million cattle globally. Nigerian medicinal plants are known to contain a large variety of chemical structures and some of the plant extracts have [...] Read more.

African trypanosomiasis is a vector-borne parasitic disease causing serious risks to the lives of about 60 million people and 48 million cattle globally. Nigerian medicinal plants are known to contain a large variety of chemical structures and some of the plant extracts have been screened for antitrypanosomal activity, in the search for potential new drugs against the illness. We surveyed the literatures on plants and plant-derived products with antitrypanosomal activity from Nigerian flora published from 1990 to 2014. About 90 plants were identified, with 54 compounds as potential active agents and presented by plant families in alphabetical order. This review indicates that the Nigerian flora may be suitable as a starting point in searching for new and more efficient trypanocidal molecules. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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14 pages, 1080 KiB

Open AccessArticle

Antileishmanial and Cytotoxic Compounds from Valeriana wallichii and Identification of a Novel Nepetolactone Derivative

by Jan Glaser¹, Martina Schultheis², Heidrun Moll², Banasri Hazra³ and Ulrike Holzgrabe^1,*

¹ Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany

² Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany

³ Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India

Molecules 2015, 20(4), 5740-5753; https://doi.org/10.3390/molecules20045740 - 1 Apr 2015

Cited by 39 | Viewed by 9128

Abstract

The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives [...] Read more.

The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2–3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6–7) and two known valtrates (compounds 8–9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, β-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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24 pages, 7225 KiB

Open AccessReview

Natural Products for the Treatment of Trachoma and Chlamydia trachomatis

by Michael G. Potroz^1,2 and Nam-Joon Cho^1,2,*

¹ School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore

² Centre for Biomimetic Sensor Science, 50 Nanyang Drive, Singapore 637553, Singapore

Molecules 2015, 20(3), 4180-4203; https://doi.org/10.3390/molecules20034180 - 5 Mar 2015

Cited by 33 | Viewed by 19860

Abstract

The neglected tropical disease (NTD) trachoma is currently the leading cause of eye disease in the world, and the pathogenic bacteria causing this condition, Chlamydia trachomatis, is also the most common sexually transmitted pathogenic bacterium. Although the serovars of this bacterial species typically [...] Read more.

The neglected tropical disease (NTD) trachoma is currently the leading cause of eye disease in the world, and the pathogenic bacteria causing this condition, Chlamydia trachomatis, is also the most common sexually transmitted pathogenic bacterium. Although the serovars of this bacterial species typically vary between ocular and genital infections there is a clear connection between genital C. trachomatis infections and the development of trachoma in infants, such that the solutions to these infections are closely related. It is the unique life cycle of the C. trachomatis bacteria which primarily leads to chronic infections and challenges in treatment using conventional antibiotics. This life cycle involves stages of infective elementary bodies (EBs) and reproductive reticulate bodies (RBs). Most antibiotics only target the reproductive RBs and this often leads to the need for prolonged therapy which facilitates the development of drug resistant pathogens. It is through combining several compounds to obtain multiple antimicrobial mechanisms that we are most likely to develop a reliable means to address all these issues. Traditional and ethnobotanical medicine provides valuable resources for the development of novel formulations and treatment regimes based on synergistic and multi-compound therapy. In this review we intend to summarize the existing literature on the application of natural compounds for controlling trachoma and inhibiting chlamydial bacteria and explore the potential for the development of new treatment modalities. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 2936 KiB

Open AccessArticle

The Role of Phosphoglycans in the Susceptibility of Leishmania mexicana to the Temporin Family of Anti-Microbial Peptides

by Gabriela A. Eggimann¹, Kathryn Sweeney¹, Hannah L. Bolt¹, Neshat Rozatian¹, Steven L. Cobb^1,* and Paul W. Denny^1,2,*

¹ Biophysical Sciences Institute, Department of Chemistry and School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK

² School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees TS17 6BH, UK

Molecules 2015, 20(2), 2775-2785; https://doi.org/10.3390/molecules20022775 - 6 Feb 2015

Cited by 27 | Viewed by 8368

Abstract

Natural product antimicrobial peptides (AMPs) have been proposed as promising agents against the Leishmania species, insect vector borne protozoan parasites causing the neglected tropical disease leishmaniasis. However, recent studies have shown that the mammalian pathogenic amastigote form of L. mexicana, a causative [...] Read more.

Natural product antimicrobial peptides (AMPs) have been proposed as promising agents against the Leishmania species, insect vector borne protozoan parasites causing the neglected tropical disease leishmaniasis. However, recent studies have shown that the mammalian pathogenic amastigote form of L. mexicana, a causative agent of cutaneous leishmaniasis, is resistant to the amphibian-derived temporin family of AMPs when compared to the insect stage promastigote form. The mode of resistance is unknown, however the insect and mammalian stages of Leishmania possess radically different cell surface coats, with amastigotes displaying low (or zero) quantities of lipophosphoglycan (LPG) and proteophosphoglycan (PPG), macromolecules which form thick a glycocalyx in promastigotes. It has been predicted that negatively charged LPG and PPG influence the sensitivity/resistance of promastigote forms to cationic temporins. Using LPG and PPG mutant L. mexicana, and an extended range of temporins, in this study we demonstrated that whilst LPG has little role, PPG is a major factor in promastigote sensitivity to the temporin family of AMPs, possibly due to the conferred anionic charge. Therefore, the lack of PPG seen on the surface of pathogenic amastigote L. mexicana may be implicated in their resistance to these peptides. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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32 pages, 4756 KiB

Open AccessReview

Natural Products as Leads in Schistosome Drug Discovery

by Bruno J. Neves^1,*, Carolina H. Andrade¹ and Pedro V. L. Cravo²

¹ LabMol—Laboratory for Drug Design and Molecular Modeling, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia 74605-170, Brazil

² GenoBio—Laboratory of Genomics and Biotechnology, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia 74605-050, Brazil

Molecules 2015, 20(2), 1872-1903; https://doi.org/10.3390/molecules20021872 - 23 Jan 2015

Cited by 74 | Viewed by 11999

Abstract

Schistosomiasis is a neglected parasitic tropical disease that claims around 200,000 human lives every year. Praziquantel (PZQ), the only drug recommended by the World Health Organization for the treatment and control of human schistosomiasis, is now facing the threat of drug resistance, indicating [...] Read more.

Schistosomiasis is a neglected parasitic tropical disease that claims around 200,000 human lives every year. Praziquantel (PZQ), the only drug recommended by the World Health Organization for the treatment and control of human schistosomiasis, is now facing the threat of drug resistance, indicating the urgent need for new effective compounds to treat this disease. Therefore, globally, there is renewed interest in natural products (NPs) as a starting point for drug discovery and development for schistosomiasis. Recent advances in genomics, proteomics, bioinformatics, and cheminformatics have brought about unprecedented opportunities for the rapid and more cost-effective discovery of new bioactive compounds against neglected tropical diseases. This review highlights the main contributions that NP drug discovery and development have made in the treatment of schistosomiasis and it discusses how integration with virtual screening (VS) strategies may contribute to accelerating the development of new schistosomidal leads, especially through the identification of unexplored, biologically active chemical scaffolds and structural optimization of NPs with previously established activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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15 pages, 1073 KiB

Open AccessArticle

Insecticidal Activities of Bark, Leaf and Seed Extracts of Zanthoxylum heitzii against the African Malaria Vector Anopheles gambiae

by Hans J. Overgaard^1,2,3, Patcharawan Sirisopa², Bertin Mikolo⁴, Karl E. Malterud^5,*, Helle Wangensteen⁵, Yuan-Feng Zou⁵, Berit S. Paulsen⁵, Daniel Massamba⁴, Stephane Duchon^2,3, Vincent Corbel^2,3 and Fabrice Chandre³

¹ Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, P.O. Box 5003, Ås 1432, Norway

² Department of Entomology, Faculty of Agriculture, Kasetsart University, 50 Ngam Wong Wan Rd, Ladyaow, Chatuchak, Bangkok 10900, Thailand

³ Institut de Recherche pour le Développement (IRD), Maladies Infectieuses et Vecteurs, Ecologie, Génétique, Evolution et Contrôle (IRD 224-CNRS 5290 UM1-UM2), Montpellier Cedex 5 34394, France

⁴ National Polytechnic High School, Marien Ngouabi University, BP 69, Brazzaville, Congo

⁵ School of Pharmacy, Department of Pharmaceutical Chemistry, Section Pharmacognosy, University of Oslo, P.O. Box 1068 Blindern, Oslo 0316, Norway

Molecules 2014, 19(12), 21276-21290; https://doi.org/10.3390/molecules191221276 - 17 Dec 2014

Cited by 18 | Viewed by 14086

Abstract

The olon tree, Zanthoxylum heitzii (syn. Fagara heitzii) is commonly found in the central-west African forests. In the Republic of Congo (Congo-Brazzaville) its bark is anecdotally reported to provide human protection against fleas. Here we assess the insecticidal activities of Z. heitzii [...] Read more.

The olon tree, Zanthoxylum heitzii (syn. Fagara heitzii) is commonly found in the central-west African forests. In the Republic of Congo (Congo-Brazzaville) its bark is anecdotally reported to provide human protection against fleas. Here we assess the insecticidal activities of Z. heitzii stem bark, seed and leaf extracts against Anopheles gambiae s.s, the main malaria vector in Africa. Extracts were obtained by Accelerated Solvent Extraction (ASE) using solvents of different polarity and by classical Soxhlet extraction using hexane as solvent. The insecticidal effects of the crude extracts were evaluated using topical applications of insecticides on mosquitoes of a susceptible reference strain (Kisumu [Kis]), a strain homozygous for the L1014F kdr mutation (kdrKis), and a strain homozygous for the G119S Ace1R allele (AcerKis). The insecticidal activities were measured using LD₅₀ and LD₉₅ and active extracts were characterized by NMR spectroscopy and HPLC chromatography. Results show that the ASE hexane stem bark extract was the most effective compound against An. gambiae (LD₅₀ = 102 ng/mg female), but was not as effective as common synthetic insecticides. Overall, there was no significant difference between the responses of the three mosquito strains to Z. heitzii extracts, indicating no cross resistance with conventional pesticides. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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22 pages, 817 KiB

Open AccessArticle

Antiprotozoal Activity against Entamoeba histolytica of Plants Used in Northeast Mexican Traditional Medicine. Bioactive Compounds from Lippia graveolens and Ruta chalepensis

by Ramiro Quintanilla-Licea^1,*, Benito David Mata-Cárdenas², Javier Vargas-Villarreal³, Aldo Fabio Bazaldúa-Rodríguez¹, Isvar Kavimngeles-Hernández¹, Jesús Norberto Garza-González³ and Magda Elizabeth Hernández-García³

¹ Universidad Autónoma de Nuevo León, UANL, Facultad de Ciencias Biológicas, Av. Universidad S/N, Cd. Universitaria, San Nicolás de los Garza, C.P. 66451 Nuevo León, Mexico

² Universidad Autónoma de Nuevo León, UANL, Facultad de Ciencias Químicas, Av. Universidad S/N, Cd. Universitaria, San Nicolás de los Garza, C.P. 66451 Nuevo León, Mexico

³ Laboratorio de Bioquímica y Biología Celular, Centro de Investigaciones Biomédicas del Noreste (CIBIN), Dos de abril esquina con San Luis Potosí, C.P. 64720 Monterrey, Mexico

Molecules 2014, 19(12), 21044-21065; https://doi.org/10.3390/molecules191221044 - 15 Dec 2014

Cited by 36 | Viewed by 12683

Abstract

Amoebiasis caused by Entamoeba histolytica is associated with high morbidity and mortality is becoming a major public health problem worldwide, especially in developing countries. Because of the side-effects and the resistance that pathogenic protozoa build against the standard antiparasitic drugs, e.g., metronidazole, much [...] Read more.

Amoebiasis caused by Entamoeba histolytica is associated with high morbidity and mortality is becoming a major public health problem worldwide, especially in developing countries. Because of the side-effects and the resistance that pathogenic protozoa build against the standard antiparasitic drugs, e.g., metronidazole, much recent attention has been paid to plants used in traditional medicine around the world in order to find new antiprotozoal agents. We collected 32 plants used in Northeast Mexican traditional medicine and the methanolic extracts of these species were screened for antiprotozoal activity against E. histolytica trophozoites using in vitro tests. Only 18 extracts showed a significant inhibiting activity and among them six plant extracts showed more than 80% growth inhibition against E. histolytica at a concentration of 150 µg/mL and the IC₅₀ values of these extracts were determined. Lippia graveolens Kunth and Ruta chalepensis Pers. showed the more significant antiprotozoal activity (91.54% and 90.50% growth inhibition at a concentration of 150 µg/mL with IC₅₀ values of 59.14 and 60.07 µg/mL, respectively). Bioassay-guided fractionation of the methanolic extracts from these two plants afforded carvacrol (1) and chalepensin (2), respectively, as bioactive compounds with antiprotozoal activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 261 KiB

Open AccessArticle

Preparation of Rotenone Derivatives and in Vitro Analysis of Their Antimalarial, Antileishmanial and Selective Cytotoxic Activities

by Yulieth Upegui¹, Juan F. Gil², Wiston Quiñones², Fernando Torres², Gustavo Escobar², Sara M. Robledo^1,3 and Fernando Echeverri^2,*

¹ PECET, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Calle 70 #52-21, Medellín 050010, Colombia

² Grupo Química Orgánica de Productos Naturales, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Calle 70 #52-21, Medellín 050010, Colombia

³ Center for Development of Products against Tropical Diseases-CIDEPRO, Medellín 050010, Colombia

Molecules 2014, 19(11), 18911-18922; https://doi.org/10.3390/molecules191118911 - 18 Nov 2014

Cited by 15 | Viewed by 8226

Abstract

Six derivatives of the known biopesticide rotenone were prepared by several chemical transformations. Rotenone and its derivatives showed differential in vitro antiparasitic activity and selective cytotoxicity. In general, compounds were more active against Plasmodium falciparum than Leishmania panamensis. Rotenone had an EC [...] Read more.

Six derivatives of the known biopesticide rotenone were prepared by several chemical transformations. Rotenone and its derivatives showed differential in vitro antiparasitic activity and selective cytotoxicity. In general, compounds were more active against Plasmodium falciparum than Leishmania panamensis. Rotenone had an EC₅₀ of 19.0 µM against P. falciparum, and 127.2 µM against L. panamensis. Although chemical transformation does not improve its biological profile against P. falciparum, three of its derivatives showed a significant level of action within an adequate range of activity with EC₅₀values < 50.0 µM. This antiplasmodial activity was not due to red blood cell hemolysis, since LC₅₀ was >>400 µM. On the other hand, all derivatives displayed a non-specific cytotoxicity on several cell lines and primary human cell cultures. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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17 pages, 679 KiB

Open AccessReview

New Uses for Old Drugs: The Tale of Artemisinin Derivatives in the Elimination of Schistosomiasis Japonica in China

by Yi-Xin Liu^1,2,3,†, Wei Wu^1,2,3,†, Yue-Jin Liang⁴, Zu-Liang Jie⁴, Hui Wang⁵, Wei Wang^1,2,3,* and Yi-Xin Huang^1,2,3,*

¹ Jiangsu Institute of Parasitic Diseases, 117 Yangxiang, Meiyuan, Wuxi 214064, China

² Key Laboratory on Technology for Parasitic Disease Prevention and Control, National Health and Family Planning Commission, 117 Yangxiang, Meiyuan, Wuxi 214064, China

³ Jiangsu Provincial Key Laboratory of Molecular Biology of Parasites, 117 Yangxiang, Meiyuan, Wuxi 214064, China

⁴ Department of Microbiology and Immunology, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA

⁵ Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX 77030, USA

^† These authors contributed equally to this work.

Molecules 2014, 19(9), 15058-15074; https://doi.org/10.3390/molecules190915058 - 19 Sep 2014

Cited by 52 | Viewed by 10203

Abstract

Artemisinin (qinghaosu), extracted from the Chinese herb Artemisia annua L. in 1972, and its three major derivatives—artemether, artesunate and dihydroartemisinin—were firstly identified as antimalarials and found active against all species of the malaria parasite. Since the early 1980s, artemisinin and its derivatives have [...] Read more.

Artemisinin (qinghaosu), extracted from the Chinese herb Artemisia annua L. in 1972, and its three major derivatives—artemether, artesunate and dihydroartemisinin—were firstly identified as antimalarials and found active against all species of the malaria parasite. Since the early 1980s, artemisinin and its derivatives have been found efficacious against Schistosoma spp., notably larval parasites, and artemisinin derivatives have played a critical role in the prevention and treatment of human schistosomiasis in China. Currently, China is moving towards the progress of schistosomiasis elimination. However, the potential development of praziquantel resistance may pose a great threat to the progress of elimination of schistosomiasis japonica in China. Fortunately, these three major artemisinin derivatives also exhibit actions against adult parasites, and reduced sensitivity to artemether, artesunate and dihydroartemisinin has been detected in praziquantel-resistant S. japonicum. In this review, we describe the application of artemisinin derivatives in the prevention and treatment of schistosomiasis japonica in China, so as to provide tools for the global agenda of schistosomiasis elimination. In addition to antimalarial and antischistosomal actions, they also show activities against other parasites and multiple cancers. Artemisinin derivatives, as old drugs identified firstly as antimalarials, continue to create new stories. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

17 pages, 753 KiB

Open AccessReview

Hinokinin, an Emerging Bioactive Lignan

by Maria Carla Marcotullio^*

, Azzurra Pelosi and Massimo Curini

Department of Pharmaceutical Sciences, University of Perugia, via del Liceo 1, 06123 Perugia, Italy

Molecules 2014, 19(9), 14862-14878; https://doi.org/10.3390/molecules190914862 - 17 Sep 2014

Cited by 42 | Viewed by 12492

Abstract

Hinokinin is a lignan isolated from several plant species that has been recently investigated in order to establish its biological activities. So far, its cytotoxicity, its anti-inflammatory and antimicrobial activities have been studied. Particularly interesting is its notable anti-trypanosomal activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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14 pages, 3503 KiB

Open AccessArticle

The in Vitro Biological Activity of the Brazilian Brown Seaweed Dictyota mertensii against Leishmania amazonensis

by Amanda Silva dos Santos Aliança¹, Keicyanne Fernanda Lessa dos Anjos¹, Thiago Nogueira De Vasconcelos Reis², Taciana Mirely Maciel Higino¹, Maria Carolina Accioly Brelaz-de-Castro³, Éverson Miguel Bianco⁴ and Regina Celia Bressan Queiroz De Figueiredo^1,*

¹ Departamento de Microbiologia, Centro de Pesquisa Aggeu Magalhães (CPqAM-FIOCRUZ), Av. Moraes Rego s/n Cidade Universitária, Campus da UFPE, Recife 50670-420, Brazil

² Departamento de Oceanografia, Universidade Federal de Pernambuco (UFPE), Recife 50740-550, Brazil

³ Departamento de Imunologia Centro de Pesquisa Aggeu Magalhães (CPqAM-FIOCRUZ), Av. Moraes Rego s/n Cidade Universitária, Campus da UFPE, Recife 50670-420, Brazil

⁴ Programa de Pós-graduação em Química, Fundação Universidade Regional de Blumenau (FURB), Campus 1, Rua Antonio da Veiga, 140, Blumenal 89012-900, Brazil

Molecules 2014, 19(9), 14052-14065; https://doi.org/10.3390/molecules190914052 - 9 Sep 2014

Cited by 24 | Viewed by 9662

Abstract

Seaweeds present a wide variety of interesting bioactive molecules. In the present work we evaluated the biological activity of the dichloromethane/methanol (2:1) extract (DME) from the brown seaweed Dictyota mertensii against Leishmania amazonensis and its cytotoxic potential on mammalian cells. The extract showed [...] Read more.

Seaweeds present a wide variety of interesting bioactive molecules. In the present work we evaluated the biological activity of the dichloromethane/methanol (2:1) extract (DME) from the brown seaweed Dictyota mertensii against Leishmania amazonensis and its cytotoxic potential on mammalian cells. The extract showed significant inhibitory effect on the growth of promastigote forms (IC₅₀ = 71.60 μg/mL) and low toxicity against mammalian cells (CC₅₀ = 233.10 μg/mL). The DME was also efficient in inhibiting the infection in macrophages, with CC₅₀ of 81.4 μg/mL and significantly decreased the survival of amastigote forms within these cells. The selectivity index showed that DME was more toxic to both promastigote (SI = 3.25) and amastigote (SI = 2.86) forms than to macrophages. Increased NO production was observed in treated macrophages suggesting that besides acting directly on the parasites, the DME also shows an immunomodulatory effect on macrophages. Drastic ultrastructural alterations consistent with loss of viability and cell death were observed in treated parasites. Confocal microscopy and cytometry analyzes showed no significant impairment of plasma membrane integrity, whereas an intense depolarization of mitochondrial membrane could be observed by using propidium iodide and rhodamine 123 staining, respectively. The low toxicity to mammalian cells and the effective activity against promastigotes and amastigotes, point to the use of DME as a promising agent for the treatment of cutaneous leishmaniasis. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 681 KiB

Open AccessArticle

In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

by Adeleke Clement Adebajo^1,2,*, Samuel Akintunde Odediran¹, Fatimah Abosede Aliyu¹, Paul Alozie Nwafor³, Ndifreke Thomas Nwoko² and Usenobong Samuel Umana²

¹ Department of Pharmacognosy, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife 220282, Osun State, Nigeria

² Department of Pharmacognosy and Herbal Medicine, Faculty of Pharmacy, University of Uyo, Uyo 520003, Akwa Ibom State, Nigeria

³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Uyo, Uyo 520003, Akwa Ibom State, Nigeria

Molecules 2014, 19(9), 13136-13146; https://doi.org/10.3390/molecules190913136 - 26 Aug 2014

Cited by 22 | Viewed by 7487

Abstract

Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected [...] Read more.

Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED₅₀ values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED₅₀ value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED₅₀ of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED₅₀ = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05) more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

17 pages, 995 KiB

Open AccessArticle

Hologram QSAR Studies of Antiprotozoal Activities of Sesquiterpene Lactones

by Gustavo H. G. Trossini^1,*, Vinícius G. Maltarollo¹ and Thomas J. Schmidt²

¹ Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Lineu Prestes, 580, 05508-000 São Paulo, Brazil

² Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, Pharma Campus, Corrensstraße 48, D-48149 Münster, Germany

Molecules 2014, 19(7), 10546-10562; https://doi.org/10.3390/molecules190710546 - 18 Jul 2014

Cited by 17 | Viewed by 8026

Abstract

Infectious diseases such as trypanosomiasis and leishmaniasis are considered neglected tropical diseases due the lack for many years of research and development into new drug treatments besides the high incidence of mortality and the lack of current safe and effective drug therapies. Natural [...] Read more.

Infectious diseases such as trypanosomiasis and leishmaniasis are considered neglected tropical diseases due the lack for many years of research and development into new drug treatments besides the high incidence of mortality and the lack of current safe and effective drug therapies. Natural products such as sesquiterpene lactones have shown activity against T. brucei and L. donovani, the parasites responsible for these neglected diseases. To evaluate structure activity relationships, HQSAR models were constructed to relate a series of 40 sesquiterpene lactones (STLs) with activity against T. brucei, T. cruzi, L. donovani and P. falciparum and also with their cytotoxicity. All constructed models showed good internal (leave-one-out q² values ranging from 0.637 to 0.775) and external validation coefficients (r²_test values ranging from 0.653 to 0.944). From HQSAR contribution maps, several differences between the most and least potent compounds were found. The fragment contribution of PLS-generated models confirmed the results of previous QSAR studies that the presence of α,β-unsatured carbonyl groups is fundamental to biological activity. QSAR models for the activity of these compounds against T. cruzi, L. donovani and P. falciparum are reported here for the first time. The constructed HQSAR models are suitable to predict the activity of untested STLs. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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15 pages, 505 KiB

Open AccessArticle

In Vivo Anti-Trypanosoma cruzi Activity of Hydro-Ethanolic Extract and Isolated Active Principles from Aristeguietia glutinosa and Mechanism of Action Studies

by Javier Varela¹, Elva Serna², Susana Torres², Gloria Yaluff², Ninfa I. Vera De Bilbao², Patricio Miño³, Ximena Chiriboga³, Hugo Cerecetto^1,*

and Mercedes González^1,*

¹ Grupo de Química Medicinal-Laboratorio de Química Orgánica-Facultad de Ciencias-Facultad de Química—UdelaR, Iguá 4225, Montevideo, C.P. 11400, Uruguay

² Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, 1120, Paraguay

³ Carrera Química Farmacéutica, Facultad de Ciencias Químicas, Universidad Central de Ecuador, Quito, C.P. 170150, Ecuador

Molecules 2014, 19(6), 8488-8502; https://doi.org/10.3390/molecules19068488 - 23 Jun 2014

Cited by 19 | Viewed by 8122

Abstract

The currently available treatments for Chagas disease show limited therapeutic potential and are associated with serious side effects. Attempting to find alternative drugs isolated from Nature as agents against Trypanosoma cruzi has been our goal. Recently, we have demonstrated the in vitro [...] Read more.

The currently available treatments for Chagas disease show limited therapeutic potential and are associated with serious side effects. Attempting to find alternative drugs isolated from Nature as agents against Trypanosoma cruzi has been our goal. Recently, we have demonstrated the in vitro anti-T. cruzi activities of two secondary metabolites isolated from the hydro-ethanolic extract of the aerial parts of Aristeguietia glutinosa (Lam.), (family Asteraceae). These active principles displayed poor hemolytic activity, low toxicity against murine macrophages, and absence of mutagenicity. Herein, proof of concept in vivo studies of the whole hydro-ethanolic extract of the aerial parts of Aristeguietia glutinosa and of the most active component isolated from the hydro-ethanolic extract, i.e., (+)-15-hydroxy-7-labden-17-al, was done in a murine acute model of Chagas disease. Both treatments caused a decrease in the animals’ parasitemia. Metabolomic mechanism of action studies were done by ¹H-NMR, both on the extract and on the active compounds, examining the effects of the metabolites both on membrane sterol biosynthesis and mitochondrial dehydrogenases, whereby we found that one of the metabolites inhibited the activity of the parasite mitochondrial dehydrogenases and the other inhibited the biosynthesis of parasite membrane sterols. The results are interesting in the context of popular use of plants for the treatment of Chagas disease. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 190 KiB

Open AccessArticle

Properties for Sourcing Nigerian Larvicidal Plants

by Adeleke Clement Adebajo, Funmilayo Gladys Famuyiwa^* and Fatima Abosede Aliyu

Department of Pharmacognosy, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife 220282, Osun State, Nigeria

Molecules 2014, 19(6), 8363-8372; https://doi.org/10.3390/molecules19068363 - 19 Jun 2014

Cited by 10 | Viewed by 8209

Abstract

Aedes aegypti is the primary vector of chikungunya, yellow and dengue fevers. Dengue fever is the major cause of child morbidity and hospitalisation in some Asian and African countries, while yellow fever is prevalent in Nigeria. The development of resistance to the available [...] Read more.

Aedes aegypti is the primary vector of chikungunya, yellow and dengue fevers. Dengue fever is the major cause of child morbidity and hospitalisation in some Asian and African countries, while yellow fever is prevalent in Nigeria. The development of resistance to the available insecticides has necessitated the continued search for safer ones from plants. Eighteen plant extracts with ethnomedical claims of or demonstrated febrifuge, antimalarial, insecticidal and insect repellent biological activities were tested for activity against the fourth instar larvae of Aedes aegypti. About 61% of the eighteen extracts demonstrated high to moderate larvicidal activity. Extracts of Piper nigrum and Abrus precatorius seeds were the most active and the larvicidal constituent(s) of the latter should be determined. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

26 pages, 450 KiB

Open AccessReview

Natural Products as Source of Potential Dengue Antivirals

by Róbson Ricardo Teixeira^1,*

, Wagner Luiz Pereira¹, Ana Flávia Costa da Silveira Oliveira^2,4, Adalberto Manoel Da Silva¹, André Silva De Oliveira^2,4, Milene Lopes Da Silva¹, Cynthia Cânedo Da Silva³ and Sérgio Oliveira De Paula^4,*

¹ Departamento de Química, Universidade Federal de Viçosa, 36570-900 Viçosa, MG, Brazil

² Instituto Federal de Educação, Ciência e Tecnologia do Norte de Minas, 39900-000 Almenara, MG, Brazil

³ Departamento de Microbiologia, Universidade Federal de Viçosa, 36570-900 Viçosa, MG, Brazil

⁴ Departamento de Biologia Geral, Universidade Federal de Viçosa, 36570-900 Viçosa, MG, Brazil

Molecules 2014, 19(6), 8151-8176; https://doi.org/10.3390/molecules19068151 - 17 Jun 2014

Cited by 68 | Viewed by 13367

Abstract

Dengue is a neglected disease responsible for 22,000 deaths each year in areas where it is endemic. To date, there is no clinically approved dengue vaccine or antiviral for human beings, even though there have been great efforts to accomplish these goals. Several [...] Read more.

Dengue is a neglected disease responsible for 22,000 deaths each year in areas where it is endemic. To date, there is no clinically approved dengue vaccine or antiviral for human beings, even though there have been great efforts to accomplish these goals. Several approaches have been used in the search for dengue antivirals such as screening of compounds against dengue virus enzymes and structure-based computational discovery. During the last decades, researchers have turned their attention to nature, trying to identify compounds that can be used as dengue antivirals. Nature represents a vast reservoir of substances that can be explored with the aim of discovering new leads that can be either used directly as pharmaceuticals or can serve as lead structures that can be optimized towards the development of new antiviral agents against dengue. In this review we describe an assortment of natural products that have been reported as possessing dengue antiviral activity. The natural products are organized into classes of substances. When appropriate, structure-activity relationships are outlined. The biological assays used to assess antiviral activity are briefly described. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 1457 KiB

Open AccessArticle

Secondary Metabolites from Vietnamese Marine Invertebrates with Activity against Trypanosoma brucei and T. cruzi

by Nguyen Phuong Thao^1,2,†

, Joo Hwan No^3,†, Bui Thi Thuy Luyen^1,2, Gyongseon Yang³, Soo Young Byun³, Junghyun Goo³, Kyung Tae Kim¹, Nguyen Xuan Cuong², Nguyen Hoai Nam², Chau Van Minh², Thomas J. Schmidt⁴

, Jong Seong Kang^1,* and Young Ho Kim^1,*

¹ College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea

² Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18-Hoang Quoc Viet, Caugiay, Hanoi 10000, Vietnam

³ Chemical Biology of Pathogens Group, Institute Pasteur Korea, Seongnam-si, Gyeonggi-do 463-400, Korea

⁴ Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstrasse 48, Münster D-48149, Germany

^† These authors contributed equally to this work.

Molecules 2014, 19(6), 7869-7880; https://doi.org/10.3390/molecules19067869 - 11 Jun 2014

Cited by 23 | Viewed by 7938

Abstract

Marine-derived natural products from invertebrates comprise an extremely diverse and promising source of the compounds from a wide variety of structural classes. This study describes the discovery of five marine natural products with activity against Trypanosoma species by natural product library screening using [...] Read more.

Marine-derived natural products from invertebrates comprise an extremely diverse and promising source of the compounds from a wide variety of structural classes. This study describes the discovery of five marine natural products with activity against Trypanosoma species by natural product library screening using whole cell in vitro assays. We investigated the anti-trypanosomal activity of the extracts from the soft corals and echinoderms living in Vietnamese seas. Of the samples screened, the methanolic extracts of several marine organisms exhibited potent activities against cultures of Trypanosoma brucei and T. cruzi (EC₅₀ < 5.0 μg/mL). Among the compounds isolated from these extracts, laevigatol B (1) from Lobophytum crassum and L. laevigatum, (24S)-ergost-4-ene-3-one (2) from Sinularia dissecta, astropectenol A (3) from Astropecten polyacanthus, and cholest-8-ene-3β,5α,6β,7α-tetraol (4) from Diadema savignyi showed inhibitory activity against T. brucei with EC₅₀ values ranging from 1.57 ± 0.14 to 14.6 ± 1.36 μM, relative to the positive control, pentamidine (EC₅₀ = 0.015 ± 0.003 μM). Laevigatol B (1) and 5α-cholest-8(14)-ene-3β,7α-diol (5) exhibited also significant inhibitory effects on T. cruzi. The cytotoxic activity of the pure compounds on mammalian cells was also assessed and found to be insignificant in all cases. This is the first report on the inhibitory effects of marine organisms collected in Vietnamese seas against Trypanosoma species responsible for neglected tropical diseases. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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11 pages, 253 KiB

Open AccessArticle

Antiprotozoal Activity of Achillea ptarmica (Asteraceae) and Its Main Alkamide Constituents

by Julia B. Althaus¹, Marcel Kaiser^2,3, Reto Brun^2,3 and Thomas J. Schmidt^1,*

¹ Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Corrensstraße 48, Münster D-48149, Germany

² Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, Basel CH-4002, Switzerland

³ University of Basel, Petersplatz 1, Basel CH-4003, Switzerland

Molecules 2014, 19(5), 6428-6438; https://doi.org/10.3390/molecules19056428 - 20 May 2014

Cited by 40 | Viewed by 8452

Abstract

In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 [...] Read more.

In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 µg/mL) and Plasmodium falciparum (IC50 = 6.6 μg/mL). Bioassay guided fractionation led to the isolation and identification of five alkamides from the most active fractions. Pellitorine and 8,9-Z-dehyropellitorine are the main components of the extract. Beside these olefinic acid amides, four alkamides with diene-diyne structures were isolated. All alkamides were tested for antiprotozoal activity in vitro. Pellitorine was the most active compound so far within this study against P. falciparum (IC50 = 3.3 µg/mL), while 8,9-Z-dehydropellitorine was most active against T. b. rhodesiense (IC50 = 2.0 µg/mL). The activity of pure pellitorine against Plasmodium is higher than that of the crude extract and thus explains the activity of the latter. None of the isolated alkamides, however, was as active against T. b. rhodesiense as the crude extract whose antitrypanosomal activity must therfore be due to a synergistic effect of the isolated compounds or to more active yet to be identified constituents. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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18 pages, 895 KiB

Open AccessArticle

Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

by Julia B. Althaus^1,†, Gerold Jerz², Peter Winterhalter²

, Marcel Kaiser^3,4, Reto Brun^3,4 and Thomas J. Schmidt^1,*

¹ Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, Pharma Campus, Corrensstraße 48, D-48149 Münster, Germany

² Institut für Lebensmittelchemie, Technische Universität Braunschweig, Schleinitzstraße 20, D-38106 Braunschweig, Germany

³ Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, CH-4002 Basel, Switzerland

⁴ University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

^† Part of the thesis of J.B.A. A preliminary account on part of this work has been published in abstract form (Planta Med. 2013, 79, 1129).

Molecules 2014, 19(5), 6184-6201; https://doi.org/10.3390/molecules19056184 - 15 May 2014

Cited by 26 | Viewed by 8043

Abstract

Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH₂Cl₂ extract from leaves of B. sempervirens showed selective in vitro activity against [...] Read more.

Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH₂Cl₂ extract from leaves of B. sempervirens showed selective in vitro activity against Plasmodium falciparum (IC₅₀ = 2.79 vs. 20.2 µg/mL for cytotoxicity against L6 rat cells). Separation of the extract by acid/base extraction into a basic and a neutral non-polar fraction led to a much more active and even more selective fraction with alkaloids while the fraction of non-polar neutral constituents was markedly less active than the crude extract. Thus, the activity of the crude extract could clearly be attributed to alkaloid constituents. Identification of the main triterpene-alkaloids and characterization of the complex pattern of this alkaloid fraction was performed by UHPLC/+ESI-QTOF-MS analyses. ESI-MS/MS target-guided larger scale preparative separation of the alkaloid fraction was performed by ‘spiral coil-countercurrent chromatography’. From the most active subfraction, the cycloartane alkaloid O-tigloylcyclovirobuxeine-B was isolated and evaluated for antiplasmodial activity which yielded an IC₅₀ of 0.455 µg/mL (cytotoxicity against L6 rat cells: IC₅₀ = 9.38 µg/mL). O-tigloylcyclovirobuxeine-B is thus most significantly responsible for the high potency of the crude extract. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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10 pages, 739 KiB

Open AccessArticle

In Vitro Leishmanicidal Activities of Sesquiterpene Lactones from Tithonia diversifolia against Leishmania braziliensis Promastigotes and Amastigotes

by Juliano S. De Toledo¹, Sergio R. Ambrósio^2,3, Carly H. G. Borges², Viviane Manfrim¹, Daniel G. Cerri¹, Angela K. Cruz¹ and Fernando B. Da Costa^3,*

¹ Department of Cell Biology, Molecular and Pathogenic Bioagents, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, SP 14049-900, Brazil

² Center for Research in Exact and Technological Sciences, University of Franca—UNIFRAN, Franca, SP 14404-600, Brazil

³ AsterBioChem Research Team, Laboratory of Pharmacognosy, Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, USP, Av. do Café s/n, Ribeirão Preto, SP 14040-903, Brazil

Molecules 2014, 19(5), 6070-6079; https://doi.org/10.3390/molecules19056070 - 14 May 2014

Cited by 37 | Viewed by 9287

Abstract

Natural compounds represent a rich and promising source of novel, biologically active chemical entities for treating leishmaniasis. Sesquiterpene lactones are a recognized class of terpenoids with a wide spectrum of biological activities, including activity against Leishmania spp. In this work, a sesquiterpene lactone-rich [...] Read more.

Natural compounds represent a rich and promising source of novel, biologically active chemical entities for treating leishmaniasis. Sesquiterpene lactones are a recognized class of terpenoids with a wide spectrum of biological activities, including activity against Leishmania spp. In this work, a sesquiterpene lactone-rich preparation—a leaf rinse extract (LRE) from Tithonia diversifolia—was tested against promastigote forms of L. braziliensis. The results revealed that the LRE is a rich source of potent leishmanicidal compounds, with an LD₅₀ value 1.5 ± 0.50 µg·mL⁻¹. Therefore, eight sesquiterpene lactones from the LRE were initially investigated against promastigote forms of L. braziliensis. One of them did not present any significant leishmanicidal effect (LD₅₀ > 50 µg·mL⁻¹). Another had a cytotoxic effect against macrophages (4.5 µg·mL⁻¹). The five leishmanicidal compounds with the highest level of selectivity were further evaluated against intracellular parasites (amastigotes) using peritoneal macrophages. Tirotundin 3-O-methyl ether, tagitinin F, and a guaianolide reduced the internalization of parasites after 48 h, in comparison with the negative control. This is the first report on sesquiterpene lactones that have potent leishmanicidal effects on both developmental stages of L. braziliensis. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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16 pages, 316 KiB

Open AccessArticle

Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae): Structure/Activity Relationships

by Thiago R. Morais¹, Thais A. Da Costa-Silva², Andre G. Tempone², Samanta Etel T. Borborema², Marcus T. Scotti³, Raquel Maria F. De Sousa⁴, Ana Carolina C. Araujo⁴, Alberto De Oliveira⁴, Sérgio Antônio L. De Morais⁴, Patricia Sartorelli¹ and João Henrique G. Lago^1,*

¹ Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP 09972270, Brazil

² Centro de Parasitologia, Instituto Adolfo Lutz, São Paulo, SP 01246902, Brazil

³ Centro de Ciências Aplicadas e Educação, Universidade Federal da Paraíba, Rio Tinto, PB 58297000, Brazil

⁴ Instituto de Química, Universidade Federal de Uberlândia, Uberlândia, MG 38400902, Brazil

Molecules 2014, 19(5), 5761-5776; https://doi.org/10.3390/molecules19055761 - 5 May 2014

Cited by 41 | Viewed by 8927

Abstract

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. [...] Read more.

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC₅₀ values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC₅₀ values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 233 KiB

Open AccessArticle

Leishmanicidal Evaluation of Tetrahydroprotoberberine and Spirocyclic Erythrina-Alkaloids

by Daniel R. Callejon^1,2, Thalita B. Riul³, Luis G. P. Feitosa^1,2, Thais Guaratini¹, Denise B. Silva¹, Achyut Adhikari^1,4, Ram L. Shrestha⁵, Lucas M. M. Marques¹

, Marcelo D. Baruffi³, João L. C. Lopes¹ and Norberto P. Lopes^1,*

¹ Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP), Universidade de São Paulo (USP), Av. Café s/n, 14040-903, Ribeirão Preto, SP, Brazil

² Lychnoflora Pesquisa e Desenvolvimento em Produtos Naturais LTDA, Ribeirão Preto 14030-090, SP, Brazil

³ Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP), Universidade de São Paulo (USP), Av. Café s/nº, 14040-903, Ribeirão Preto, SP, Brazil

⁴ Research Institute of Chemistry, ICCBS, University of Karachi, Karachi 75270, Pakistan

⁵ Amrit Science Campus, Tribhuvan University, Kathmandu, Nepal

Molecules 2014, 19(5), 5692-5703; https://doi.org/10.3390/molecules19055692 - 5 May 2014

Cited by 40 | Viewed by 9220

Abstract

Leishmaniasis is one of the World’s most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and [...] Read more.

Leishmaniasis is one of the World’s most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and seven alkaloids 3–9, were obtained from Erythrina verna. The structures of the compounds were confirmed by mass spectrometry and 1D- and 2D-NMR spectroscopy. The leishmanicidal activity of compounds 1–9 against Leishmania amazonensis was tested on promastigote forms and cytotoxicity against J774 (macrophage cell line) was assessed in vitro. Compound 1 showed potent activity (IC₅₀ = 0.18 µg/mL), compared with the standard amphotericin B (IC₅₀ = 0.20 µg/mL). The spirocyclic erythrina-alkaloids showed lower leishmanicidal activity than dibenzoquinolizine type alkaloids. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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20 pages, 3850 KiB

Open AccessArticle

In-Silico Analyses of Sesquiterpene-Related Compounds on Selected Leishmania Enzyme-Based Targets

by Freddy A. Bernal and Ericsson Coy-Barrera^*

Laboratorio de Química Bioorgánica, Departamento de Química, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Cundinamarca 250240, AA 49300, Colombia

Molecules 2014, 19(5), 5550-5569; https://doi.org/10.3390/molecules19055550 - 29 Apr 2014

Cited by 32 | Viewed by 9177

Abstract

A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve [...] Read more.

A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve sesquiterpene-based drug design. The present in silico study allows us to make important observations about the molecular details of the binding modes of a set of antileishmanial sesquiterpenes against four drug-enzyme targets [pteridine reductase-1 (PTR1), N-myristoyl transferase (NMT), cysteine synthase (CS), trypanothione synthetase (TryS)]. Through molecular docking it was found that two sesquiterpene coumarins are promising leads for the PTR1 and TryS inhibition purposes, and some xanthanolides also exhibited better affinity towards PTR1 and CS binding. In addition, the affinity values were clustered by Principal Component Analysis and drug-like properties were analyzed for the strongest-docking sesquiterpenes. The results are an excellent starting point for future studies of structural optimization of this kind of compounds. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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8 pages, 218 KiB

Open AccessArticle

Two Trypanocidal Dipeptides from the Roots of Zapoteca portoricensis (Fabaceae)

by Ngozi Justina Nwodo^1,*, Festus Basden C. Okoye², Daowan Lai³, Abdessamad Debbab³, Reto Brun^4,5 and Peter Proksch³

¹ Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, 410001 Nsukka, Enugu State, Nigeria

² Department of Pharmaceutical and Medicinal Chemistry, Nnamdi Azikiwe University, 420281 Awka, Anambra State, Nigeria

³ Institute for Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University, D-40225 Dusseldorf, Germany

⁴ Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Insitute, CH-4002 Basel, Switzerland

⁵ Department of Medical Parasitology, University of Basel, CH-4003 Basel, Switzerland

Molecules 2014, 19(5), 5470-5477; https://doi.org/10.3390/molecules19055470 - 25 Apr 2014

Cited by 28 | Viewed by 7943

Abstract

Zapoteca portoricensis (Jacq) HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) [...] Read more.

Zapoteca portoricensis (Jacq) HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) and anabellamide, were isolated from the methanol root extract of Zapoteca portoricensis and their chemical structures deduced by one dimensional and two dimensional NMR and mass spectrometry. These compounds were isolated for the first time from this plant, and no report has been found on their previous isolation from the genus Zapoteca. Evaluation of their trypanocidal activity showed that compound 1 exhibited potent activity against Trypanosoma brucei rhodesiense with an IC50 value of 3.63 μM and selectivity index of 25.3. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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14 pages, 970 KiB

Open AccessArticle

A Benzoic Acid Derivative and Flavokawains from Piper species as Schistosomiasis Vector Controls

by Ludmila N. Rapado^1,2,*, Giovana C. Freitas³, Adriano Polpo⁴, Maritza Rojas-Cardozo⁵, Javier V. Rincón⁵, Marcus T. Scotti⁶

, Massuo J. Kato³, Eliana Nakano^1,*,† and Lydia F. Yamaguchi^3,†

¹ Laboratório de Parasitologia, Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP, CEP 05503-900, Brazil

² Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo, SP, CEP 05508-000, Brazil

³ Research Support Center in Diversity of Natural Products, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, sala 1124, São Paulo, SP, CEP 05508-000, Brazil

⁴ Departamento de Estatística, Centro de Ciências Exatas e de Tecnologia, Universidade Federal de São Carlos, Via Washington Luís, km 235, Sao Carlos, SP, Caixa-postal 676, CEP 13565-905, Brazil

⁵ Department of Pharmacy, Faculty of Sciences, Universidad Nacional de Colombia, Kr 30 45-03, Bogotá, Colombia

⁶ Centro de Ciências Aplicadas e Educação, Universidade Federal da Paraíba, Campus IV, Rua da Mangueira, s/n, Rio Tinto, PB, CEP 5829-7000, Brazil

^† These authors contributed equally to the organization of this article.

Molecules 2014, 19(4), 5205-5218; https://doi.org/10.3390/molecules19045205 - 23 Apr 2014

Cited by 12 | Viewed by 7908

Abstract

The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic [...] Read more.

The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic acid derivative and three flavokawains from Piper diospyrifolium, P. cumanense and P. gaudichaudianum displayed significant activities against Biomphalaria glabrata snails. Additionally, “in silico” studies were performed using docking assays and Molecular Interaction Fields to evaluate the physical-chemical differences among the compounds in order to characterize the observed activities of the test compounds against Biomphalaria glabrata snails. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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12 pages, 224 KiB

Open AccessArticle

Antiprotozoal Activities of Millettia richardiana (Fabaceae) from Madagascar

by Manitriniaina Rajemiarimiraho^1,2,3, Jean-Théophile Banzouzi^2,4,*, Marie-Laure Nicolau-Travers^5,6,7, Suzanne Ramos⁴, Zakaria Cheikh-Ali⁸, Christian Bories⁸, Olga L. Rakotonandrasana², Stéphane Rakotonandrasana¹, Philippe Antoine Andrianary³ and Françoise Benoit-Vical^5,6,7,*

¹ Centre National d'Application de la Recherche Pharmaceutique (CNARP), BP 702 Antananarivo 101, Madagascar, France

² Centre d'Etude et de Recherche Médecins d'Afrique (CERMA), 43, rue des Glycines, 91600 Savigny sur Orge, France

³ Ecole Supérieure Polytechnique d'Antananarivo (ESPA), Université d'Antananarivo, BP 1500, Antananarivo 101, Madagascar

⁴ Institut de Chimie des Substances Naturelles (ICSN-CNRS), Bâtiment 27, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France

⁵ CNRS/LCC (Laboratoire de Chimie de Coordination) UPR8241, 205, route de Narbonne, F-31077 Toulouse, France

⁶ Université de Toulouse III, UPS, LCC; 118, route de Narbonne, F-31077 Toulouse, France

⁷ Service de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Rangueil, Université de Toulouse et Faculté de Médecine de Rangueil, Université de Toulouse III, UPS, TSA 50032, 31059 Toulouse cedex 9, France

⁸ Laboratoire de Pharmacognosie et de Chimiothérapie Antiparasitaire, CNRS UMR 8076 BioCIS, Faculté de Pharmacie, 5 rue J.-B. Clément, Université Paris-Sud 11, 92296 Châtenay-Malabry, France

Molecules 2014, 19(4), 4200-4211; https://doi.org/10.3390/molecules19044200 - 3 Apr 2014

Cited by 8 | Viewed by 7617

Abstract

With at least 60% of the Millettia species (Fabaceae) being in medicinal use, we found it relevant to assess the potential antiprotozoal and antifungal activities of Millettia richardiana. Water and methanol crude extracts of the stem barks from M. richardiana and the six [...] Read more.

With at least 60% of the Millettia species (Fabaceae) being in medicinal use, we found it relevant to assess the potential antiprotozoal and antifungal activities of Millettia richardiana. Water and methanol crude extracts of the stem barks from M. richardiana and the six fractions resulting from the fractionation of the methanol extract were tested. The dichloromethane extracted fraction showed the best in vitro antiprotozoal activities (IC₅₀ = 5.8 μg/mL against Plasmodium falciparum, 11.8 μg/mL against Leishmania donovani and 12.8 μg/mL against Trypanosoma brucei brucei) as well as low cytotoxicity on several cell lines. The phytochemical analysis showed this selected fraction to be rich in terpenoids and alkaloids, which could explain its antiparasitic activity. A phytochemical study revealed the presence of lonchocarpenin, betulinic acid, β-amyrin, lupeol, palmitic acid, linoleic acid and stearic acid, among which betulinic acid and lupeol could be the compounds responsible of these antiprotozoal activities. By contrast, neither the crude extracts nor the fractions showed antifungal activity against Candida. These results confirm the importance of the genus Millettia in Malagasy ethnomedicine, its potential use in antiparasitic therapy, and the interest of developing a sustainable exploitation of this plant. Moreover, both molecules betulinic acid and lupeol appeared as very relevant molecules for their antiprotozoal properties. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

11 pages, 1080 KiB

Open AccessArticle

Antischistosomal Activity of the Terpene Nerolidol

by Marcos P.N. Silva¹, George L.S. Oliveira², Rusbene B.F. De Carvalho³, Damião P. De Sousa⁴

, Rivelilson M. Freitas^2,3, Pedro L.S. Pinto⁵ and Josué De Moraes^1,*

¹ Faculdade de Ciências de Guarulhos (FACIG/UNIESP), Av. Guarulhos, 1844, Guarulhos, SP 07025-000, Brazil

² Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Piauí, Teresina, PI 64049-550, Brazil

³ Programa de Pós-graduação em Biotecnologia, Universidade Federal do Piauí, Teresina, PI 64049-550, Brazil

⁴ Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil

⁵ Enteroparasitas, Instituto Adolfo Lutz, São Paulo, SP 01246-902, Brazil

Molecules 2014, 19(3), 3793-3803; https://doi.org/10.3390/molecules19033793 - 24 Mar 2014

Cited by 59 | Viewed by 9195

Abstract

Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people worldwide. Since the treatment of this disease currently relies on a single drug, praziquantel, new and safe schistosomicidal agents are urgently required. Nerolidol, a sesquiterpene present in the essential oils [...] Read more.

Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people worldwide. Since the treatment of this disease currently relies on a single drug, praziquantel, new and safe schistosomicidal agents are urgently required. Nerolidol, a sesquiterpene present in the essential oils of several plants, is found in many foods and was approved by the U.S. Food and Drug Administration. In this study we analysed the in vitro antiparasitic effect of nerolidol on Schistosoma mansoni adult worms. Nerolidol at concentrations of 31.2 and 62.5 μM reduced the worm motor activity and caused the death of all male and female schistosomes, respectively. In addition, confocal laser scanning microscopy revealed morphological alterations on the tegument of worms such as disintegration, sloughing and erosion of the surface, and a correlation between viability and tegumental damage was observed. In conclusion, nerolidol may be a promising lead compound for the development of antischistosomal natural agents. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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16 pages, 294 KiB

Open AccessArticle

Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

by Stefanie Zimmermann^1,2, Gerda Fouché³, Maria De Mieri¹, Yukiko Yoshimoto⁴, Toyonobu Usuki⁴

, Rudzani Nthambeleni³, Christopher J. Parkinson⁵, Christiaan Van der Westhuyzen³

, Marcel Kaiser^2,6, Matthias Hamburger¹

and Michael Adams^1,*

¹ Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland

² Department Medical Parasitology & Infection Biology, Swiss TPH, Socinstrasse 57, 4000 Basel, Switzerland

³ CSIR Biosciences, Meiring Naudé Road, Brummeria, Pretoria 0001, Gauteng, South Africa

⁴ Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda, Tokyo 102-8554, Japan

⁵ School of Biomedical Sciences, Charles Sturt University, Orange, NSW 2800, Australia

⁶ University of Basel, Petersplatz 1, 4003 Basel, Switzerland

Molecules 2014, 19(3), 3523-3538; https://doi.org/10.3390/molecules19033523 - 21 Mar 2014

Cited by 37 | Viewed by 9748

Abstract

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and [...] Read more.

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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17 pages, 387 KiB

Open AccessArticle

Synthetic Fosmidomycin Analogues with Altered Chelating Moieties Do Not Inhibit 1-Deoxy-D-xylulose 5-phosphate Reductoisomerase or Plasmodium falciparum Growth In Vitro

by René Chofor¹, Martijn D.P. Risseeuw¹, Jenny Pouyez², Chinchu Johny³, Johan Wouters², Cynthia S. Dowd⁴, Robin D. Couch³ and Serge Van Calenbergh^1,*

¹ Laboratory for Medicinal Chemistry, Ghent University, Harelbekestraat 72, Ghent B-9000, Belgium

² Department of Chemistry, University of Namur, UNamur, Rue de Bruxelles 61, Namur B-5000, Belgium

³ Department of Chemistry and Biochemistry, George Mason University, Manassas, VA 20110, USA

⁴ Department of Chemistry, George Washington University, Washington, DC 20052, USA

Molecules 2014, 19(2), 2571-2587; https://doi.org/10.3390/molecules19022571 - 24 Feb 2014

Cited by 17 | Viewed by 8417

Abstract

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or [...] Read more.

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or the Plasmodia. This study further underlines the importance of the hydroxamate functionality and illustrates that identifying effective alternative bidentate ligands for this target enzyme is challenging. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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17 pages, 451 KiB

Open AccessArticle

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

by Jan Glaser¹, Martina Schultheis², Sudipta Hazra³, Banasri Hazra³, Heidrun Moll², Uta Schurigt^2,* and Ulrike Holzgrabe^1,*

¹ Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg 97074, Germany

² Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Str. 2, Würzburg 97080, Germany

³ Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India

Molecules 2014, 19(2), 1394-1410; https://doi.org/10.3390/molecules19021394 - 27 Jan 2014

Cited by 31 | Viewed by 9844

Abstract

Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC [...] Read more.

Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC₅₀ = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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