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Pharmaceutics
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Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases
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Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 51846

Special Issue Editor

Dr. Maria João Gouveia

E-Mail Website
Guest Editor
1. Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Centre for the Study in Animal Science (CECA), University of Porto, Praça do Coronel Pacheco 42, 4050-083 Porto, Portugal
2. Centre for Parasite Biology and Immunology, Department of Infectious Diseases, National Health Institute Dr. Ricardo Jorge, Rua Alexandre Herculano 321, 4000-055 Porto, Portugal
Interests: carcinogenesis; helminth-associated carcinogenesis; combine therapy; immunotherapy; protein recombinant; parasites; schistosoma; opisthorchis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Parasitic infections such as malaria, schistosomiasis, and leishmaniasis, among others, remain a major public health problem causing substantial mortality and morbidity worldwide. Antiparasitic drugs are available, but they are not ideal and present major disadvantages. Furthermore, there is a real concern regarding the development of drug resistance (e.g., primaquine for malaria). Few novel antiparasitic drugs have emerged in recent decades, and the discovery and development of novel antiparasitic drugs are urgently needed. Strategies such as combinations of existing drugs, improvements to known drugs, de novo discovery, and/or the exploration of natural bioactive compounds, among others, should be explored to improve the treatment of parasitic infections and prevent the development of drug resistance.

This Special Issue aims to discuss the strategies for the discovery and development of novel treatments for parasitic diseases. The design and synthesis of novel drugs or drug derivatives and their antiparasitic activities, structure–activity relationships (SARs), the use of bioinformatics tools (or others) for the discovery of potential drugs, and natural compounds as sources of antiparasitic drugs will be addressed here. Colleagues are invited to submit original research papers, communications, or review articles to this Special Issue.

Dr. Maria João Castro Gouveia
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • parasites
  • drug synthesis and discovery
  • natural bioactive compounds
  • drug combinations
  • parasitic diseases
  • neglected tropical diseases
  • novel therapeutic strategies
  • optimization
  • formulations
  • mechanism of action
  • screening assays
  • pharmacodynamics
  • pharmacokinetics
  • drug resistance
  • antiparasitic activity

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Published Papers (26 papers)

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15 pages, 2065 KiB  
Article
Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
by Anand Chakroborty, Deiniol R. Pritchard, Marc E. Bouillon, Anna Cervi, Rolf Kraehenbuehl, Charlotte Wild, Caroline Fenn, Peter Holdsworth, Colin Capner, Gilda Padalino, Josephine E. Forde-Thomas, Joseph Payne, Brendan G. Smith, Maggie Fisher, Martina Lahmann, Mark S. Baird and Karl F. Hoffmann
Pharmaceutics 2023, 15(7), 1869; https://doi.org/10.3390/pharmaceutics15071869 - 03 Jul 2023
Viewed by 1881
Abstract
Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in [...] Read more.
Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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26 pages, 4802 KiB  
Article
Using ChEMBL to Complement Schistosome Drug Discovery
by Gilda Padalino, Avril Coghlan, Giampaolo Pagliuca, Josephine E. Forde-Thomas, Matthew Berriman and Karl F. Hoffmann
Pharmaceutics 2023, 15(5), 1359; https://doi.org/10.3390/pharmaceutics15051359 - 28 Apr 2023
Cited by 3 | Viewed by 1464
Abstract
Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant [...] Read more.
Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant schistosomes developing. Considerable time and effort could be saved in the schistosome drug discovery pipeline if available functional genomics, bioinformatics, cheminformatics and phenotypic resources are systematically leveraged. Our approach, described here, outlines how schistosome-specific resources/methodologies, coupled to the open-access drug discovery database ChEMBL, can be cooperatively used to accelerate early-stage, schistosome drug discovery efforts. Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range. Three of those compounds (epoxomicin, CGP60474 and staurosporine) also demonstrated potent and fast-acting ex vivo effects on adult schistosomes and completely inhibited egg production. ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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11 pages, 818 KiB  
Article
Antiplasmodial Activity of Hydroalcoholic Extract from Jucá (Libidibia ferrea) Pods
by Francisco Flávio Vieira de Assis, José Sousa de Almeida Junior, Tânia Mara Pires Moraes, Fernando de Pilla Varotti, Camila Castilho Moraes, Adilson Sartoratto, Waldiney Pires Moraes and Antonio Humberto Hamad Minervino
Pharmaceutics 2023, 15(4), 1162; https://doi.org/10.3390/pharmaceutics15041162 - 06 Apr 2023
Viewed by 1148
Abstract
Malaria is an infectious and parasitic disease caused by protozoa of the genus Plasmodium, which affects millions of people in tropical and subtropical areas. Recently, there have been multiple reports of drug resistance in Plasmodium populations, leading to the search for potential [...] Read more.
Malaria is an infectious and parasitic disease caused by protozoa of the genus Plasmodium, which affects millions of people in tropical and subtropical areas. Recently, there have been multiple reports of drug resistance in Plasmodium populations, leading to the search for potential new active compounds against the parasite. Thus, we aimed to evaluate the in vitro antiplasmodial activity and cytotoxicity of the hydroalcoholic extract of Jucá (Libidibia ferrea) in serial concentrations. Jucá was used in the form of a freeze-dried hydroalcoholic extract. For the cytotoxicity assay, the(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) method with the WI-26VA4 human cell line was used. For the antiplasmodial activity, Plasmodium falciparum synchronized cultures were treated with serial concentrations (0.2 to 50 μg/mL) of the Jucá extract. In terms of the chemical composition of the Jucá extract, gas chromatography coupled to mass spectrometry measurements revealed the main compounds as ellagic acid, valoneic acid dilactone, gallotannin, and gallic acid. The Jucá hydroalcoholic extract did not show cytotoxic activity per MTT, with an IC50 value greater than 100 µg/mL. Regarding the antiplasmodial activity, the Jucá extract presented an IC50 of 11.10 µg/mL with a selective index of nine. Because of its antiplasmodial activity at the tested concentrations and low toxicity, the Jucá extract is presented as a candidate for herbal medicine in the treatment of malaria. To the best of our knowledge, this is the first report of antiplasmodial activity in Jucá. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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18 pages, 3638 KiB  
Article
Poly-ε-Caprolactone Implants for Benznidazole Prolonged Release: An Alternative to Chagas Disease Oral Treatment
by Ana Lia Mazzeti, Karolina R. Gonçalves, Patrícia Ferreira Boasquívis, Jamile Barbosa, Bruno G. Pereira, Maria de Nazaré Correia Soeiro, Vanessa Carla Furtado Mosqueira and Maria Terezinha Bahia
Pharmaceutics 2023, 15(4), 1126; https://doi.org/10.3390/pharmaceutics15041126 - 02 Apr 2023
Viewed by 1269
Abstract
Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-ɛ-caprolactone (PCL) is proposed [...] Read more.
Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-ɛ-caprolactone (PCL) is proposed in this study for a controlled release of BZ and to improve patient compliance. The BZ–PCL implants were characterized by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, which indicated that BZ remains in its crystalline state dispersed in the polymer matrix with no polymorphic transitions. BZ–PCL implants, even at the highest doses, induce no alteration of the levels of hepatic enzymes in treated animals. BZ release from implants to blood was monitored in plasma during and after treatment in healthy and infected animals. Implants at equivalent oral doses increase the body’s exposure to BZ in the first days compared with oral therapy, exhibiting a safe profile and allowing sustained BZ concentrations in plasma to induce a cure of all mice in the experimental model of acute infection by the Y strain of T. cruzi. BZ–PCL implants have the same efficacy as 40 daily oral doses of BZ. Biodegradable BZ implants are a promising option to reduce failures related to poor adherence to treatment, with more comfort for patients, and with sustained BZ plasma concentration in the blood. These results are relevant for optimizing human Chagas disease treatment regimens. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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17 pages, 3288 KiB  
Article
Derivatives of Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Hepatic Stage of Plasmodium berghei Infection In Vitro
by Kateřina Hradiská Breiterová, Aneta Ritomská, Diana Fontinha, Jana Křoustková, Daniela Suchánková, Anna Hošťálková, Marcela Šafratová, Eliška Kohelová, Rozálie Peřinová, Rudolf Vrabec, Denise Francisco, Miguel Prudêncio and Lucie Cahlíková
Pharmaceutics 2023, 15(3), 1007; https://doi.org/10.3390/pharmaceutics15031007 - 21 Mar 2023
Cited by 2 | Viewed by 1123
Abstract
The incidence rate of malaria and the ensuing mortality prompts the development of novel antimalarial drugs. In this work, the activity of twenty-eight Amaryllidaceae alkaloids (1–28) belonging to seven different structural types was assessed, as well as twenty semisynthetic derivatives of [...] Read more.
The incidence rate of malaria and the ensuing mortality prompts the development of novel antimalarial drugs. In this work, the activity of twenty-eight Amaryllidaceae alkaloids (1–28) belonging to seven different structural types was assessed, as well as twenty semisynthetic derivatives of the β-crinane alkaloid ambelline (28a–28t) and eleven derivatives of the α-crinane alkaloid haemanthamine (29a–29k) against the hepatic stage of Plasmodium infection. Six of these derivatives (28h, 28m, 28n and 28r–28t) were newly synthesized and structurally identified. The most active compounds, 11-O-(3,5-dimethoxybenzoyl)ambelline (28m) and 11-O-(3,4,5-trimethoxybenzoyl)ambelline (28n), displayed IC50 values in the nanomolar range of 48 and 47 nM, respectively. Strikingly, the derivatives of haemanthamine (29) with analogous substituents did not display any significant activity, even though their structures are quite similar. Interestingly, all active derivatives were strictly selective against the hepatic stage of infection, as they did not demonstrate any activity against the blood stage of Plasmodium infection. As the hepatic stage is a bottleneck of the plasmodial infection, liver-selective compounds can be considered crucial for further development of the malaria prophylactics. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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14 pages, 1179 KiB  
Article
Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents against Trypanosoma cruzi
by Mariana C. Pagotti, Herbert J. Dias, Ana Carolina B. B. Candido, Thaís A. S. Oliveira, Alexandre Borges, Nicoli D. Oliveira, Carla D. Lopes, Renato P. Orenha, Renato L. T. Parreira, Antônio E. M. Crotti and Lizandra G. Magalhães
Pharmaceutics 2023, 15(3), 754; https://doi.org/10.3390/pharmaceutics15030754 - 24 Feb 2023
Cited by 2 | Viewed by 1653
Abstract
Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type [...] Read more.
Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type neolignans (DBNs) and two benzofuran-type neolignans (BNs) were synthesized and evaluated against amastigote forms of two Trypanosoma cruzi strains. The in vitro cytotoxicity and hemolytic activity of the most active compounds were also evaluated and their relationships with T. cruzi tubulin DBNs were investigated by an in silico approach. Four DBNs demonstrated activity against the T. cruzi Tulahuen lac-Z strain (IC50 from 7.96 to 21.12 µM), and DBN 1 exhibited the highest activity against the amastigote forms of the T. cruzi Y strain (IC50 3.26 μM). Compounds 1–4 showed CC50 values higher than antitrypanosomal activities, except for DBN 3. All DBNs with antitrypanosomal activity demonstrated CH50 higher than 100 µM. The in silico results indicated that DBNs 1, 2, and 4 are capable of destabilizing the dynamics of the tubulin-microtubule from the vinca site. These compounds displayed promising in vitro activity against T. cruzi, especially compound 1, and can be considered molecular prototypes for the development of new antiparasitic drugs. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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15 pages, 2860 KiB  
Article
Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes
by Carlos F. M. Silva, Teresa Leão, Filipa Dias, Ana M. Tomás, Diana C. G. A. Pinto, Eduardo F. T. Oliveira, Ana Oliveira, Pedro A. Fernandes and Artur M. S. Silva
Pharmaceutics 2023, 15(2), 669; https://doi.org/10.3390/pharmaceutics15020669 - 16 Feb 2023
Cited by 2 | Viewed by 1108
Abstract
Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has [...] Read more.
Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48). Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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16 pages, 4739 KiB  
Article
Anti-Trypanosoma cruzi Properties of Sesquiterpene Lactones Isolated from Stevia spp.: In Vitro and In Silico Studies
by Jimena Borgo, Orlando G. Elso, Jessica Gomez, Mauro Coll, Cesar A. N. Catalán, Juan Mucci, Guzmán Alvarez, Lía M. Randall, Patricia Barrera, Emilio L. Malchiodi, Augusto E. Bivona, María Florencia Martini and Valeria P. Sülsen
Pharmaceutics 2023, 15(2), 647; https://doi.org/10.3390/pharmaceutics15020647 - 15 Feb 2023
Cited by 3 | Viewed by 1620
Abstract
Stevia species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds, S. satureiifolia var. satureiifolia and S. alpina were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, [...] Read more.
Stevia species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds, S. satureiifolia var. satureiifolia and S. alpina were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, were isolated. These compounds were assessed in vitro against Trypanosoma cruzi stages, showing IC50 values of 11.80 and 4.98 on epimastigotes, 56.08 and 26.19 on trypomastigotes and 4.88 and 20.20 µM on amastigotes, respectively. Cytotoxicity was evaluated on Vero cells by the MTT assay. The effect of the compounds on trypanothyone reductase (TcTR), Trans-sialidase (TcTS) and the prolyl oligopeptidase of 80 kDa (Tc80) as potential molecular targets of T. cruzi was investigated. Santhemoidin C inhibited oligopeptidase activity when tested against recombinant Tc80 using a fluorometric assay, reaching an IC50 of 34.9 µM. Molecular docking was performed to study the interaction between santhemoidin C and the Tc80 protein, reaching high docking energy levels. Plasma membrane shedding and cytoplasmic vacuoles, resembling autophagosomes, were detected by transmission microscopy in parasites treated with santhemoidin C. Based on these results, santhemoidin C represents a promising candidate for further studies in the search for new molecules for the development of trypanocidal drugs. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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24 pages, 7485 KiB  
Article
Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in Mesocestoides vogae (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles
by Gabriela Hrčková, Terézia Mačak Kubašková, Dagmar Mudroňová, Zuzana Jurčacková and Denisa Ciglanová
Pharmaceutics 2023, 15(2), 541; https://doi.org/10.3390/pharmaceutics15020541 - 06 Feb 2023
Cited by 1 | Viewed by 1525
Abstract
The model flatworm Mesocestoides vogae proliferating stage of infection elicits immunosuppression in the host. It was used to investigate the effects of human leukocyte extract (DLE) alone and in combination with anthelmintic albendazole (ABZ) on the reduction in peritoneal infection, peritoneal exudate cells [...] Read more.
The model flatworm Mesocestoides vogae proliferating stage of infection elicits immunosuppression in the host. It was used to investigate the effects of human leukocyte extract (DLE) alone and in combination with anthelmintic albendazole (ABZ) on the reduction in peritoneal infection, peritoneal exudate cells (PECs), their adherent counterparts, and peritoneal exudates after the termination of therapy. Balb/c mice were infected with the larvae of M. vogae. PECs and adherent macrophages were studied via flow cytometry, mRNA transcript levels, and immunofluorescence. The cytokine levels were measured via ELISA and larvae were counted. ABZ significantly reduced larval counts (581.2 ± 65, p < 0.001), but the highest reduction was observed after combined treatment with ABZ and DLE (389.2 ± 119, p < 0.001) in comparison with the control. Compared to an infected group, the proportions of CD11b+CD19- myeloid cells with suppressive ability decreased after albendazole (ABZ) in combination with DLE, which was the most effective in the elevation of B cells and CD11b+F4/80mid/highMHCIIhigh macrophages/monocytes (22.2 ± 5.4%). Transcripts of the M2 macrophage markers (arginase 1, FIZZ-1, and Ym-1) were downregulated after DLE and combined therapy but not after ABZ, and the opposite trend was seen for iNOS. This contrasts with reduced ex vivo NO production by LPS-stimulated PECs from DLE and ABZ+DLE groups, where adherent macrophages/monocytes had elevated transcripts of the INF-γ receptor and STAT1 and reduced expression of STAT3, STAT6, and IL-10. Each therapy differentially modulated transcription profiles and concentrations of IFN-γ, TNF-α, IL-12p40, IL-6, IL-10, and TGF-β cytokines. DLE strongly ameliorated ABZ-induced suppression of INF-γ and IL-12 and preserved downregulation for IL-4, IL-10, and TGF-β. Epigenetic study on adherent macrophages from infected mice showed that ABZ, ABZ-sulfoxide, and DLE could interact with the mRNA of examined markers in a dose-dependent pattern. Co-administration of DLE with ABZ seemed to augment the drug’s larvicidal effect via modulation of immunity. In comparison with ABZ, combined therapy was the most effective in alleviating parasite-induced Th2/Treg/STAT3/STA6 directed immunosuppression by stimulating the Th1 cytokines, M1 macrophage polarization, and activation of the IFNγ/STAT1 signaling pathway. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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19 pages, 12539 KiB  
Article
Parasitological, Molecular, and Histopathological Investigation of the Potential Activity of Propolis and Wheat Germ Oil against Acute Toxoplasmosis in Mice
by Ashraf Mohamed Barakat, Khaled A. Abd El-Razik, Hassan Ali Mohamed El Fadaly, Walaa M. Saleh, Fatma Abo Zakaib Ali, Asmaa Aboelabbas Gouda, Sabry A. S. Sadek, Naief Dahran, Manal F. El-khadragy and Ehab Kotb Elmahallawy
Pharmaceutics 2023, 15(2), 478; https://doi.org/10.3390/pharmaceutics15020478 - 01 Feb 2023
Cited by 2 | Viewed by 1806
Abstract
Toxoplasmosis is one of the most common parasitic zoonoses that affects all vertebrates. The drugs most commonly used against toxoplasmosis have many side effects, making the development of new antiparasitic drugs a big challenge. The present study evaluated the therapeutic effectiveness of novel [...] Read more.
Toxoplasmosis is one of the most common parasitic zoonoses that affects all vertebrates. The drugs most commonly used against toxoplasmosis have many side effects, making the development of new antiparasitic drugs a big challenge. The present study evaluated the therapeutic effectiveness of novel herbal treatments, including propolis and wheat germ oil (WGO), against acute toxoplasmosis. A total of 50 albino mice were divided into five groups: group 1 (G1) (non-infected and non-treated); group 2 (G2) (infected without treatment); group 3 (G3) (treated with propolis); group 4 (G4) (treated with WGO); group 5 (G5) (treated with a combination of propolis and WGO). The effects of the herbal substances on different organs, mainly liver, spleen, and lungs, were investigated using parasitological, molecular, and histopathological examinations. The results of parasitological examination demonstrated statistically significant (p < 0.05) differences in the parasitic load between treated groups (G3, G4, and G5) compared to the control positive group (G2). These differences were represented by a significant reduction in the parasite load in stained tissue smears from the liver obtained from the animals treated with propolis (G3) compared to the parasite load in the positive control group. Similarly, animals (G4) treated with WGO exhibited a significant reduction in the parasite load versus the positive control group, while the lowest parasite load was found in G5, treated with propolis and WGO. Quantification of the parasite burden through molecular methods (PCR) revealed similar findings represented by reduction in the parasite burden in all treated groups with WGO and propolis as compared to the control group. Importantly, these previous parasitological and molecular findings were accompanied by a marked improvement in the histopathological picture of the liver, spleen, and lungs. In conclusion, propolis and WGO showed a good combination of therapeutic efficacy against acute toxoplasmosis. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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14 pages, 1617 KiB  
Article
Polyphenolic Profile of Herniaria hemistemon Aerial Parts Extract and Assessment of Its Anti-Cryptosporidiosis in a Murine Model: In Silico Supported In Vivo Study
by Mosad A. Ghareeb, Mansour Sobeh, Tarek Aboushousha, Marwa Esmat, Hala Sh. Mohammed and Eman S. El-Wakil
Pharmaceutics 2023, 15(2), 415; https://doi.org/10.3390/pharmaceutics15020415 - 26 Jan 2023
Cited by 12 | Viewed by 1439
Abstract
Herniaria hemistemon J.Gay is widely used in folk medicine to treat hernia. The present study aimed to annotate the phytoconstituents of H. hemistemon aerial-part extract and investigate its in vivo anticryptosporidial activity. The chemical characterization was achieved via the LC–ESI–MS/MS technique resulting in [...] Read more.
Herniaria hemistemon J.Gay is widely used in folk medicine to treat hernia. The present study aimed to annotate the phytoconstituents of H. hemistemon aerial-part extract and investigate its in vivo anticryptosporidial activity. The chemical characterization was achieved via the LC–ESI–MS/MS technique resulting in the annotation of 37 phytocompounds comprising flavonoids and phenolic acids. Regarding the anticryptosporidial activity, fifty dexamethasone-immunosuppressed mice were separated into five groups: GI, un-infected (normal control); GII, infected but not treated (model); GIII, infected and received NTZ, the reference drug; GIV, infected and received H. hemistemon extract (100 mg/kg); and GV, infected and received H. hemistemon extract (200 mg/kg). When GIII, GIV, and GV were compared to GII, parasitological analyses displayed highly significant differences in the mean numbers of Cryptosporidium parvum oocysts in the stool between the different groups. GV demonstrated the highest efficacy of 79%. Histopathological analyses displayed improvement in the small intestine and liver pathology in the treated groups (GIII, IV, and V) related to the model (GII), with GV showing the highest efficacy. Moreover, the docking-based study tentatively highlighted the potential of benzoic acid derivatives as lactate dehydrogenase inhibitors. The docked compounds showed the same binding interactions as oxamic acid, where they established H-bond interactions with ARG-109, ASN-140, ASP-168, ARG-171, and HIS-195. To sum up, H. hemistemon is a promising natural therapeutic agent for cryptosporidiosis. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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10 pages, 1417 KiB  
Article
In Vivo Safety and Efficacy of Chalcone-Loaded Microparticles with Modified Polymeric Matrix against Cutaneous Leishmaniasis
by Ariane de J. Sousa-Batista, Natalia Arruda-Costa, Wallace Pacienza-Lima, Felipe Carvalho-Gondim, Rosiane F. Santos, Silvia A. G. Da-Silva, Maria Inês Ré and Bartira Rossi-Bergmann
Pharmaceutics 2023, 15(1), 51; https://doi.org/10.3390/pharmaceutics15010051 - 24 Dec 2022
Viewed by 1372
Abstract
Current chemotherapy of cutaneous leishmaniasis (CL) is based on repeated systemic or intralesional administration of drugs that often cause severe toxicity. Previously, we demonstrated the therapeutic potential of biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) loaded with 8% of the nitrochalcone CH8 (CH8/PLGA) prepared [...] Read more.
Current chemotherapy of cutaneous leishmaniasis (CL) is based on repeated systemic or intralesional administration of drugs that often cause severe toxicity. Previously, we demonstrated the therapeutic potential of biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) loaded with 8% of the nitrochalcone CH8 (CH8/PLGA) prepared by a conventional bench method. Aiming at an industrially scalable process and increased drug loading, new MPs were prepared by spray drying: CH8/PDE with PLGA matrix and CH8/PVDE with PLGA + polyvinylpyrrolidone (PVP) matrix, both with narrower size distribution and higher drug loading (18%) than CH8/PLGA. Animal studies were conducted to evaluate their clinical feasibility. Both MP types induced transient local swelling and inflammation, peaking at 1–2 days, following a single intralesional injection. Different from CH8/PDE that released 90% of the drug in the ear tissue in 60 days, CH8/PVDE achieved that in 30 days. The therapeutic efficacy of a single intralesional injection was evaluated in BALB/c mice infected with Leishmania (Leishmania) amazonensis and golden hamsters infected with L. (Viannia) braziliensis. CH8/PVDE promoted greater reduction in parasite burden than CH8/PDE or CH8/PLGA, measured at one month and two months after the treatment. Thus, addition of PVP to PLGA MP matrix accelerates drug release in vivo and increases its therapeutic effect against CL. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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14 pages, 2279 KiB  
Article
Isopropyl Gallate, a Gallic Acid Derivative: In Silico and In Vitro Investigation of Its Effects on Leishmania major
by Danielly Silva de Melo, José Arimatéa de Oliveira Nery Neto, Maisa de Sousa dos Santos, Vinícius Duarte Pimentel, Rita de Cássia Viana Carvalho, Valéria Carlos de Sousa, Ruy Gabriel Costa Sousa, Lázaro Gomes do Nascimento, Michel Muálem de Moraes Alves, Daniel Dias Rufino Arcanjo, Damião Pergentino de Sousa and Fernando Aécio de Amorim Carvalho
Pharmaceutics 2022, 14(12), 2701; https://doi.org/10.3390/pharmaceutics14122701 - 02 Dec 2022
Cited by 3 | Viewed by 1483
Abstract
Isopropyl gallate (IPG) is a polyphenol obtained from alterations in the gallic acid molecule via acid catalysis with previously reported leishmanicidal and trypanocidal activities. The present study aims to evaluate in silico binding activity towards some targets for antileishmanial chemotherapy against Leishmania major [...] Read more.
Isopropyl gallate (IPG) is a polyphenol obtained from alterations in the gallic acid molecule via acid catalysis with previously reported leishmanicidal and trypanocidal activities. The present study aims to evaluate in silico binding activity towards some targets for antileishmanial chemotherapy against Leishmania major species, and ADMET parameters for IPG, as well as in vitro antileishmanial and cytotoxic effects. Molecular docking was performed using AutoDockVina and BIOVIA Discovery Studio software, whereas in silico analysis used SwissADME, PreADMET and admetSAR software. In vitro antileishmanial activity on promastigotes and amastigotes of Leishmania major, cytotoxicity and macrophages activation were assessed. IPG exhibited affinity for pteridine reductase (PTR1; −8.2 kcal/mol) and oligopeptidase B (OPB; −8.0 kcal/mol) enzymes. ADMET assays demonstrated good lipophilicity, oral bioavailability, and skin permeability, as well as non-mutagenic, non-carcinogenic properties and low risk of cardiac toxicity for IPG. Moreover, IPG inhibited the in vitro growth of promastigotes (IC50 = 90.813 µM), presented significant activity against amastigotes (IC50 = 13.45 μM), promoted low cytotoxicity in macrophages (CC50 = 1260 μM), and increased phagocytic capacity. These results suggest IPG is more selectively toxic to the parasite than to mammalian cells. IPG demonstrated acceptable in silico pharmacokinetics parameters, and reduced infection and infectivity in parasitized macrophages, possibly involving macrophage activation pathways and inhibition of leishmania enzymes. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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13 pages, 1523 KiB  
Article
Methylene Blue-Based Combination Therapy with Amodiaquine Prevents Severe Malaria in an Experimental Rodent Model
by Jérôme Dormoi, Rémy Amalvict, Mathieu Gendrot and Bruno Pradines
Pharmaceutics 2022, 14(10), 2031; https://doi.org/10.3390/pharmaceutics14102031 - 24 Sep 2022
Cited by 2 | Viewed by 1447
Abstract
Untreated malaria can progress rapidly to severe forms (<24 h). Moreover, resistance to antimalarial drugs is a threat to global efforts to protect people from malaria. Given this, it is clear that new chemotherapy must be developed. We contribute new data about using [...] Read more.
Untreated malaria can progress rapidly to severe forms (<24 h). Moreover, resistance to antimalarial drugs is a threat to global efforts to protect people from malaria. Given this, it is clear that new chemotherapy must be developed. We contribute new data about using methylene blue (MB) to cure malaria and cerebral malaria in a combined therapy with common antimalarial drugs, including mefloquine (MQ) and amodiaquine (AQ). A C57BL6/J mouse model was used in an experimental cerebral malaria model. Mice were infected with Plasmodium berghei ANKA on Day 0 (D0) and the treatment started on D3 (nearly 1% parasitaemia) with AQ, MQ or MB alone or in combination with AQ or MQ. AQ, MQ and MB alone were unable to prevent cerebral malaria as part of a late chemotherapy. MB-based combination therapies were efficient even if treatment began at a late stage. We found a significant difference in survival rate (p < 0.0001) between MBAQ and the untreated group, but also with the AQ (p = 0.0024) and MB groups (p < 0.0001). All the infected mice treated with MB in combination with AQ were protected from cerebral malaria. Partial protection was demonstrated with MB associated with MQ. In this group, a significant difference was found between MBMQ and the untreated group (p < 0.0001), MQ (p = 0.0079) and MB (p = 0.0039). MB associated with AQ would be a good candidate for preventing cerebral malaria. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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18 pages, 8556 KiB  
Article
Schistosome Sulfotransferases: Mode of Action, Expression and Localization
by Meghan A. Guzman, Anastasia Rugel, Sevan N. Alwan, Reid Tarpley, Alexander B. Taylor, Frédéric D. Chevalier, George R. Wendt, James J. Collins III, Timothy J. C. Anderson, Stanton F. McHardy and Philip T. LoVerde
Pharmaceutics 2022, 14(7), 1416; https://doi.org/10.3390/pharmaceutics14071416 - 06 Jul 2022
Cited by 3 | Viewed by 1524
Abstract
Oxamniquine (OXA) is a prodrug activated by a sulfotransferase (SULT) that was only active against Schistosoma mansoni. We have reengineered OXA to be effective against S. haematobium and S. japonicum. Three derivatives stand out, CIDD-0066790, CIDD-0072229, and CIDD-0149830 as [...] Read more.
Oxamniquine (OXA) is a prodrug activated by a sulfotransferase (SULT) that was only active against Schistosoma mansoni. We have reengineered OXA to be effective against S. haematobium and S. japonicum. Three derivatives stand out, CIDD-0066790, CIDD-0072229, and CIDD-0149830 as they kill all three major human schistosome species. However, questions remain. Is the OXA mode of action conserved in derivatives? RNA-interference experiments demonstrate that knockdown of the SmSULT, ShSULT, and SjSULT results in resistance to CIDD-0066790. Confirming that the OXA-derivative mode of action is conserved. Next is the level of expression of the schistosome SULTs in each species, as well as changes in SULT expression throughout development in S. mansoni. Using multiple tools, our data show that SmSULT has higher expression compared to ShSULT and SjSULT. Third, is the localization of SULT in the adult, multicellular eucaryotic schistosome species. We utilized fluorescence in situ hybridization and uptake of radiolabeled OXA to determine that multiple cell types throughout the adult schistosome worm express SULT. Thus, we hypothesize the ability of many cells to express the sulfotransferase accounts for the ability of the OXA derivatives to kill adult worms. Our studies demonstrate that the OXA derivatives are able to kill all three human schistosome species and thus will be a useful complement to PZQ. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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21 pages, 8987 KiB  
Article
Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum
by Patrícia de A. Machado, Pollyanna S. Gomes, Monique P. D. Carneiro, Victor Midlej, Elaine S. Coimbra and Herbert L. de Matos Guedes
Pharmaceutics 2022, 14(7), 1373; https://doi.org/10.3390/pharmaceutics14071373 - 29 Jun 2022
Viewed by 1515
Abstract
Studies have previously demonstrated the importance of serine proteases in Leishmania. A well-known serine protease inhibitor, TPCK, was used in the present study to evaluate its in vitro and in vivo antileishmanial effects and determine its mechanism of action. Despite slight toxicity [...] Read more.
Studies have previously demonstrated the importance of serine proteases in Leishmania. A well-known serine protease inhibitor, TPCK, was used in the present study to evaluate its in vitro and in vivo antileishmanial effects and determine its mechanism of action. Despite slight toxicity against mammalian cells (CC50 = 138.8 µM), TPCK was selective for the parasite due to significant activity against L. amazonensis and L. infantum promastigote forms (IC50 = 14.6 and 31.7 µM for L. amazonensis PH8 and Josefa strains, respectively, and 11.3 µM for L. infantum) and intracellular amastigotes (IC50 values = 14.2 and 16.6 µM for PH8 and Josefa strains, respectively, and 21.7 µM for L. infantum). Leishmania parasites treated with TPCK presented mitochondrial alterations, oxidative stress, modifications in lipid content, flagellar alterations, and cytoplasmic vacuoles, all of which are factors that could be considered as contributing to the death of the parasites. Furthermore, BALB/c mice infected with L. amazonensis and treated with TPCK had a reduction in lesion size and parasite loads in the footpad and spleen. In BALB/c mice infected with L. infantum, TPCK also caused a reduction in the parasite loads in the liver and spleen. Therefore, we highlight the antileishmanial effect of the assessed serine protease inhibitor, proposing a potential therapeutic target in Leishmania as well as a possible new alternative treatment for leishmaniasis. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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34 pages, 11697 KiB  
Article
The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel
by Yash Gupta, Neha Sharma, Snigdha Singh, Jesus G. Romero, Vinoth Rajendran, Reagan M. Mogire, Mohammad Kashif, Jordan Beach, Walter Jeske, Poonam, Bernhards R. Ogutu, Stefan M. Kanzok, Hoseah M. Akala, Jennifer Legac, Philip J. Rosenthal, David J. Rademacher, Ravi Durvasula, Agam P. Singh, Brijesh Rathi and Prakasha Kempaiah
Pharmaceutics 2022, 14(7), 1371; https://doi.org/10.3390/pharmaceutics14071371 - 28 Jun 2022
Cited by 1 | Viewed by 2793
Abstract
Malaria elimination urgently needs novel antimalarial therapies that transcend resistance, toxicity, and high costs. Our multicentric international collaborative team focuses on developing multistage antimalarials that exhibit novel mechanisms of action. Here, we describe the design, synthesis, and evaluation of a novel multistage antimalarial [...] Read more.
Malaria elimination urgently needs novel antimalarial therapies that transcend resistance, toxicity, and high costs. Our multicentric international collaborative team focuses on developing multistage antimalarials that exhibit novel mechanisms of action. Here, we describe the design, synthesis, and evaluation of a novel multistage antimalarial compound, ‘Calxinin’. A compound that consists of hydroxyethylamine (HEA) and trifluoromethyl-benzyl-piperazine. Calxinin exhibits potent inhibitory activity in the nanomolar range against the asexual blood stages of drug-sensitive (3D7), multidrug-resistant (Dd2), artemisinin-resistant (IPC4912), and fresh Kenyan field isolated Plasmodium falciparum strains. Calxinin treatment resulted in diminished maturation of parasite sexual precursor cells (gametocytes) accompanied by distorted parasite morphology. Further, in vitro liver-stage testing with a mouse model showed reduced parasite load at an IC50 of 79 nM. A single dose (10 mg/kg) of Calxinin resulted in a 30% reduction in parasitemia in mice infected with a chloroquine-resistant strain of the rodent parasite P. berghei. The ex vivo ookinete inhibitory concentration within mosquito gut IC50 was 150 nM. Cellular in vitro toxicity assays in the primary and immortalized human cell lines did not show cytotoxicity. A computational protein target identification pipeline identified a putative P. falciparum membrane protein (Pf3D7_1313500) involved in parasite calcium (Ca2+) homeostasis as a potential Calxinin target. This highly conserved protein is related to the family of transient receptor potential cation channels (TRP-ML). Target validation experiments showed that exposure of parasitized RBCs (pRBCs) to Calxinin induces a rapid release of intracellular Ca2+ from pRBCs; leaving de-calcinated parasites trapped in RBCs. Overall, we demonstrated that Calxinin is a promising antimalarial lead compound with a novel mechanism of action and with potential therapeutic, prophylactic, and transmission-blocking properties against parasites resistant to current antimalarials. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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20 pages, 2211 KiB  
Article
A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis
by Caroline De Souza Pereira, Helenita Costa Quadros, Samuel Yaw Aboagye, Diana Fontinha, Sarah D’Alessandro, Margaret Elizabeth Byrne, Mathieu Gendrot, Isabelle Fonta, Joel Mosnier, Diogo Rodrigo M. Moreira, Nicoletta Basilico, David L. Williams, Miguel Prudêncio, Bruno Pradines and Maribel Navarro
Pharmaceutics 2022, 14(6), 1251; https://doi.org/10.3390/pharmaceutics14061251 - 12 Jun 2022
Cited by 5 | Viewed by 2221
Abstract
Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine [...] Read more.
Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF6. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the Plasmodium life cycle. The source of this activity was thoroughly investigated by comparing parasite susceptibility to the hybrid’s components, the annotation of structure–activity relationships and studies of the mechanism of action. The activity of [AuAQPQ]PF6 for the parasite’s asexual blood stages was influenced by the presence of AQ, while its activity against gametocytes and pre-erythrocytic parasites was influenced by both quinolinic components. Moreover, the coordination of ligands to gold(I) was found to be essential for the enhancement of potency, as suggested by the observation that a combination of quinolinic ligands does not reproduce the antimalarial potency and efficacy as observed for the metallic hybrid. Our results indicate that this gold(I) hybrid compound presents a dual mechanism of action by inhibiting the beta-hematin formation and enzymatic activity of thioredoxin reductases. Overall, our findings support the potential of transition metals as a dual chemical linker and an antiplasmodial payload for the development of hybrid-based drugs. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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20 pages, 2530 KiB  
Article
New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase
by Christian Espinosa-Bustos, Mariana Ortiz Pérez, Alonzo Gonzalez-Gonzalez, Ana María Zarate, Gildardo Rivera, Javier A. Belmont-Díaz, Emma Saavedra, Mauricio A. Cuellar, Karina Vázquez and Cristian O. Salas
Pharmaceutics 2022, 14(6), 1121; https://doi.org/10.3390/pharmaceutics14061121 - 25 May 2022
Cited by 8 | Viewed by 1785
Abstract
To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of Trypanosoma cruzi strains (NINOA and INC-5) and on J774 [...] Read more.
To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of Trypanosoma cruzi strains (NINOA and INC-5) and on J774 murine macrophages. The design of the new naphthoquinone derivatives considered the incorporation of nitrogenous fragments with different substitution patterns present in compounds with activity on T. cruzi, and, thus, 19 compounds were synthesised in a simple manner. Compounds 2e and 7j showed the lowest IC50 values (0.43 µM against both strains for 2e and 0.19 µM and 0.92 µM for 7j). Likewise, 7j was more potent than the reference drug, benznidazole, and was more selective on epimastigotes. To postulate a possible mechanism of action, molecular docking studies were performed on T. cruzi trypanothione reductase (TcTR), specifically at a site in the dimer interface, which is a binding site for this type of naphthoquinone. Interestingly, 7j was one of the compounds that showed the best interaction profile on the enzyme; therefore, 7j was evaluated on TR, which behaved as a non-competitive inhibitor. Finally, 7j was predicted to have a good pharmacokinetic profile for oral administration. Thus, the naphthoquinone nucleus should be considered in the search for new trypanocidal agents based on our hit 7j. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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15 pages, 3759 KiB  
Article
Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
by Markéta Zajíčková, Lukáš Prchal, Ivan Vokřál, Linh Thuy Nguyen, Thomas Kurz, Robin Gasser, Klára Bednářová, Magdalena Mičundová, Beate Lungerich, Oliver Michel and Lenka Skálová
Pharmaceutics 2022, 14(4), 754; https://doi.org/10.3390/pharmaceutics14040754 - 30 Mar 2022
Viewed by 1741
Abstract
As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 and [...] Read more.
As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 and HBK4, that are active against H. contortus larvae. The present study was designed to assess the activity of these compounds against H. contortus eggs and adults, hepatotoxicity in rats and sheep, as well as biotransformation in H. contortus adults and the ovine liver. Both compounds exhibited no inhibitory effect on the hatching of eggs. The benzyloxy amide BLK127 significantly decreased the viability of adults in sensitive and resistant strains of H. contortus and showed no hepatotoxic effect, even at the highest concentration tested (100 µM). In contrast, HBK4 had no impact on the viability of H. contortus adults and exhibited significant hepatotoxicity. Based on these findings, HBK4 was excluded from further studies, while BLK127 seems to be a potential candidate for a new anthelmintic. Consequently, biotransformation of BLK127 was tested in H. contortus adults and the ovine liver. In H. contortus, several metabolites formed via hydroxylation, hydrolysis and glycosidation were identified, but the extent of biotransformation was low, and the total quantity of the metabolites formed did not differ significantly between the sensitive and resistant strains. In contrast, ovine liver cells metabolized BLK127 more extensively with a glycine conjugate of 4-(pentyloxy)benzoic acid as the main BLK127 metabolite. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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Review

Jump to: Research, Other

25 pages, 1980 KiB  
Review
BRCT Domains: Structure, Functions, and Implications in Disease—New Therapeutic Targets for Innovative Drug Discovery against Infections
by José Peña-Guerrero, Celia Fernández-Rubio, Alfonso T. García-Sosa and Paul A. Nguewa
Pharmaceutics 2023, 15(7), 1839; https://doi.org/10.3390/pharmaceutics15071839 - 27 Jun 2023
Cited by 3 | Viewed by 1604
Abstract
The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these [...] Read more.
The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these functions, BRCT domains are able to interact with DNA and proteins. Moreover, such domains are also implicated in several pathogenic processes and malignancies including breast, ovarian, and lung cancer. Although these domains exhibit moderately conserved folding, their sequences show very low conservation. Interestingly, sequence variations among species are considered positive traits in the search for suitable therapeutic targets, since non-specific drug interactions might be reduced. These main characteristics of BRCT, as well as its critical implications in key biological processes in the cell, have prompted the study of these domains as therapeutic targets. This review explores the possible roles of BRCT domains as therapeutic targets for drug discovery. We describe their common structural features and relevant interactions and pathways, as well as their implications in pathologic processes. Drugs commonly used to target these domains are also presented. Finally, based on their structures, we describe new drug design possibilities using modern and innovative techniques. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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14 pages, 771 KiB  
Review
Novel Therapeutics for Malaria
by Haitham Alaithan, Nirbhay Kumar, Mohammad Z. Islam, Angelike P. Liappis and Victor E. Nava
Pharmaceutics 2023, 15(7), 1800; https://doi.org/10.3390/pharmaceutics15071800 - 23 Jun 2023
Cited by 2 | Viewed by 2408
Abstract
Malaria is a potentially fatal disease caused by protozoan parasites of the genus Plasmodium. It is responsible for significant morbidity and mortality in endemic countries of the tropical and subtropical world, particularly in Africa, Southeast Asia, and South America. It is estimated that [...] Read more.
Malaria is a potentially fatal disease caused by protozoan parasites of the genus Plasmodium. It is responsible for significant morbidity and mortality in endemic countries of the tropical and subtropical world, particularly in Africa, Southeast Asia, and South America. It is estimated that 247 million malaria cases and 619,000 deaths occurred in 2021 alone. The World Health Organization’s (WHO) global initiative aims to reduce the burden of disease but has been massively challenged by the emergence of parasitic strains resistant to traditional and emerging antimalarial therapy. Therefore, development of new antimalarial drugs with novel mechanisms of action that overcome resistance in a safe and efficacious manner is urgently needed. Based on the evolving understanding of the physiology of Plasmodium, identification of potential targets for drug intervention has been made in recent years, resulting in more than 10 unique potential anti-malaria drugs added to the pipeline for clinical development. This review article will focus on current therapies as well as novel targets and therapeutics against malaria. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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19 pages, 1398 KiB  
Review
Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections
by Ellen Wasan, Tavonga Mandava, Pablo Crespo-Moran, Adrienne Nagy and Kishor M. Wasan
Pharmaceutics 2022, 14(11), 2316; https://doi.org/10.3390/pharmaceutics14112316 - 28 Oct 2022
Cited by 5 | Viewed by 2708
Abstract
Amphotericin B (AmpB) is a polyene macrolide antibiotic used in the treatment of blood-borne parasitic and fungal infections. However, its use, particularly in the developing world, has been limited by dose-dependent kidney toxicity, other systemic-related toxicity issues following injection, the inconvenience of parenteral [...] Read more.
Amphotericin B (AmpB) is a polyene macrolide antibiotic used in the treatment of blood-borne parasitic and fungal infections. However, its use, particularly in the developing world, has been limited by dose-dependent kidney toxicity, other systemic-related toxicity issues following injection, the inconvenience of parenteral administration, and accessibility. Oral formulation approaches have focused on the dual problem of solubility and permeability of AmpB, which is poorly water soluble, amphoteric and has extremely low oral bioavailability. Therefore, to enhance oral absorption, researchers have employed micellar formulations, polymeric nanoparticles, cochleates, pro-drugs, and self-emulsifying drug delivery systems (SEDDS). This paper will highlight current uses of AmpB against parasitic infections such as leishmaniasis, preclinical and clinical formulation strategies, applications in veterinary medicine and the importance of developing a cost-effective and safe oral AmpB formulation. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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25 pages, 1331 KiB  
Review
Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates
by Surbhi Jain, Utkarsha Sahu, Awanish Kumar and Prashant Khare
Pharmaceutics 2022, 14(8), 1590; https://doi.org/10.3390/pharmaceutics14081590 - 30 Jul 2022
Cited by 10 | Viewed by 3431
Abstract
Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the [...] Read more.
Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective anti-leishmanial through pointing to new drug targets in less time, having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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19 pages, 2617 KiB  
Review
Chemical and Pharmacological Properties of Decoquinate: A Review of Its Pharmaceutical Potential and Future Perspectives
by Tainá Santos Souza, Diogo Rodrigo Magalhães Moreira and Henrique Rodrigues Marcelino
Pharmaceutics 2022, 14(7), 1383; https://doi.org/10.3390/pharmaceutics14071383 - 30 Jun 2022
Cited by 3 | Viewed by 1960
Abstract
Decoquinate (DQ) is an antimicrobial agent commonly used as a feed additive for birds for human consumption. Its use as an additive is well established, but DQ has the potential for therapy as an antimicrobial drug for veterinary treatment and its optimized derivatives [...] Read more.
Decoquinate (DQ) is an antimicrobial agent commonly used as a feed additive for birds for human consumption. Its use as an additive is well established, but DQ has the potential for therapy as an antimicrobial drug for veterinary treatment and its optimized derivatives and/or formulations, mainly nanoformulations, have antimicrobial activity against pathogens that infect humans. However, DQ has a high partition coefficient and low solubility in aqueous fluids, and these biopharmaceutical properties have limited its use in humans. In this review, we highlight the antimicrobial activity and pharmacokinetic properties of DQ and highlight the solutions currently under investigation to overcome these drawbacks. A literature search was conducted focusing on the use of decoquinate against various infectious diseases in humans and animals. The search was conducted in several databases, including scientific and patent databases. Pharmaceutical nanotechnology and medicinal chemistry are the tools of choice to achieve human applications, and most of these applications have been able to improve the biopharmaceutical properties and pharmacokinetic profile of DQ. Based on the results presented here, DQ prototypes could be tested in clinical trials for human application in the coming years. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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40 pages, 6248 KiB  
Systematic Review
Antiparasitic Activity of Tea Tree Oil (TTO) and Its Components against Medically Important Ectoparasites: A Systematic Review
by Solomon Abrha Bezabh, Wubshet Tesfaye, Julia K. Christenson, Christine F. Carson and Jackson Thomas
Pharmaceutics 2022, 14(8), 1587; https://doi.org/10.3390/pharmaceutics14081587 - 29 Jul 2022
Cited by 5 | Viewed by 5523
Abstract
Ectoparasites are pathogens that can infect the skin and cause immense pain, discomfort, and disease. They are typically managed with insecticides. However, the fast-emerging antimicrobial resistance and the slow rate of development of new bio-actives combined with environmental and health concerns over the [...] Read more.
Ectoparasites are pathogens that can infect the skin and cause immense pain, discomfort, and disease. They are typically managed with insecticides. However, the fast-emerging antimicrobial resistance and the slow rate of development of new bio-actives combined with environmental and health concerns over the continued use of neurotoxic insecticides warrant newer and alternative methods of control. Tea tree oil (TTO), as an alternative agent, has shown remarkable promise against ectoparasites in recent studies. To our knowledge, this is the first systematic review to assess preclinical and clinical studies exploring the antiparasitic activity of TTO and its components against clinically significant ectoparasites, such as Demodex mites, scabies mites, house dust mites, lice, fleas, chiggers, and bed bugs. We systematically searched databases, including PubMed, MEDLINE (EBSCOhost), Embase (Scopus), CENTRAL, Cochrane Library, CINAHL, ScienceDirect, Web of Science, SciELO, and LILACS in any language from inception to 4 April 2022. Studies exploring the therapeutic activity of TTO and its components against the ectoparasites were eligible. We used the ToxRTool (Toxicological data reliability assessment) tool, the Joanna Briggs Institute (JBI) critical appraisal tools, and the Jadad scale to assess the methodological qualities of preclinical (in vitro and in vivo) studies, non-randomised controlled trials (including cohort, case series, and case studies), and randomised controlled trials, respectively. Of 497 identified records, 71 studies were included in this systematic review, and most (66%) had high methodological quality. The findings of this review revealed the promising efficacy of TTO and its components against ectoparasites of medical importance. Most importantly, the compelling in vitro activity of TTO against ectoparasites noted in this review seems to have translated well into the clinical environment. The promising outcomes observed in clinical studies provide enough evidence to justify the use of TTO in the pharmacotherapy of ectoparasitic infections. Full article
(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)
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