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Special Issue "Emerging Drug Discovery Approaches against Infectious Diseases"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 8 November 2017

Special Issue Editors

Guest Editor
Prof. Dr. Diego Muñoz-Torrero

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, Barcelona E-08028, Spain
Website | E-Mail
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
Guest Editor
Prof. Dr. Kelly Chibale

Department of Chemistry, Institute of Infectious Disease and Molecular Medicine, and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa
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Interests: antiparasitic and antibacterial drug discovery; antimalarial agents; antituberculosis agents; antischistosomiasis agents; drug repositioning; efflux pump inhibitors

Special Issue Information

Dear Colleagues,

This Special Issue is related to the 1st Molecules Medicinal Chemistry Symposium (MMCS 2017), which will be held on 8 September, 2017, at the Faculty of Pharmacy and Food Sciences of the University of Barcelona.

Infectious diseases inflict tremendous human suffering, especially in the most disfavored countries, where they cause a huge economic burden that hampers their way out of poverty. Efficacy and safety issues, as well as the rapid emergence of drug resistance in human pathogens, undermine the clinical usefulness of many currently available drugs, thereby making the development of novel anti-infective drugs a dire need and anti-infective drug discovery a hot research front.

Participants of the symposium, as well as all researchers working in the field, are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which report on the design, synthesis, and evaluation of novel drug candidates against bacterial, protozoan, viral, and fungal infections, the identification of novel biological targets or therapeutic approaches, or studies about resistance mechanisms and strategies to circumvent them.

Prof. Dr. Diego Muñoz-Torrero
Prof. Dr. Kelly Chibale
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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

  • Structure-based drug design
  • Ligand-based drug design
  • Drug synthesis
  • Target-based assays
  • Phenotypic screening
  • Target validation
  • Drug resistance
  • Resistance mechanisms

Published Papers (14 papers)

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Research

Open AccessArticle Screening a Natural Product-Based Library against Kinetoplastid Parasites
Molecules 2017, 22(10), 1715; doi:10.3390/molecules22101715
Received: 5 September 2017 / Revised: 4 October 2017 / Accepted: 4 October 2017 / Published: 12 October 2017
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Abstract
Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the
[...] Read more.
Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments. In this study, the Davis open access natural product-based library was screened against kinetoplastids (Leishmania donovani DD8, Trypanosoma brucei brucei and Trypanosoma cruzi) using phenotypic assays. The aim of this study was to identify hit compounds, with a focus on improved efficacy, selectivity and potential to target several kinetoplastid parasites. The IC50 values of the natural products were obtained for L. donovani DD8, T. b. brucei and T. cruzi in addition to cytotoxicity against the mammalian cell lines, HEK-293, 3T3 and THP-1 cell lines were determined to ascertain parasite selectivity. Thirty-one compounds were identified with IC50 values of ≤ 10 µM against the kinetoplastid parasites tested. Lissoclinotoxin E (1) was the only compound identified with activity across all three investigated parasites, exhibiting IC50 values < 5 µM. In this study, natural products with the potential to be new chemical starting points for drug discovery efforts for kinetoplastid diseases were identified. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Nano-Formulation of Ethambutol with Multifunctional Graphene Oxide and Magnetic Nanoparticles Retains Its Anti-Tubercular Activity with Prospects of Improving Chemotherapeutic Efficacy
Molecules 2017, 22(10), 1697; doi:10.3390/molecules22101697
Received: 24 September 2017 / Accepted: 3 October 2017 / Published: 12 October 2017
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Abstract
Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization’s recommended frontline chemotherapy against TB. However, the lengthy
[...] Read more.
Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization’s recommended frontline chemotherapy against TB. However, the lengthy treatment regimens consisting of a cocktail of antibiotics affect patient compliance. There is an urgent need to improve the current therapy so as to reduce treatment duration and dosing frequency. In this study, we have designed a novel anti-TB multifunctional formulation by fabricating graphene oxide with iron oxide magnetite nanoparticles serving as a nano-carrier on to which ethambutol was successfully loaded. The designed nanoformulation was characterised using various analytical techniques. The release of ethambutol from anti-TB multifunctional nanoparticles formulation was found to be sustained over a significantly longer period of time in phosphate buffer saline solution at two physiological pH (7.4 and 4.8). Furthermore, the nano-formulation showed potent anti-tubercular activity while remaining non-toxic to the eukaryotic cells tested. The results of this in vitro evaluation of the newly designed nano-formulation endorse its further development in vivo. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Antibacterial and Antitubercular Activities of Cinnamylideneacetophenones
Molecules 2017, 22(10), 1685; doi:10.3390/molecules22101685
Received: 30 August 2017 / Revised: 2 October 2017 / Accepted: 3 October 2017 / Published: 10 October 2017
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Abstract
Cinnamaldehyde is a natural product with broad spectrum of antibacterial activity. In this work, it was used as a template for design and synthesis of a series of 17 cinnamylideneacetophenones. Phenolic compounds 3 and 4 exhibited MIC (minimum inhibitory concentration) and MBC (minimum
[...] Read more.
Cinnamaldehyde is a natural product with broad spectrum of antibacterial activity. In this work, it was used as a template for design and synthesis of a series of 17 cinnamylideneacetophenones. Phenolic compounds 3 and 4 exhibited MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) values of 77.9 to 312 µM against Staphylococcus aureus, Streptococcus mutans, and Streptococcus sanguinis. Compounds 2, 7, 10, and 18 presented potent effects against Mycobacterium tuberculosis (57.2 µM ≤ MIC ≤ 70.9 µM). Hydrophilic effects caused by substituents on ring B increased antibacterial activity against Gram-positive species. Thus, log Po/w were calculated by using high-performance liquid chromatography-photodiode array detection (HPLC-PDA) analyses, and cinnamylideneacetophenones presented values ranging from 2.5 to 4.1. In addition, the effects of 3 and 4 were evaluated on pulmonary cells, indicating their moderate toxicity (46.3 µM ≤ IC50 ≤ 96.7 µM) when compared with doxorubicin. Bioactive compounds were subjected to in silico prediction of pharmacokinetic properties, and did not violate Lipinski’s and Veber’s rules, corroborating their potential bioavailability by an oral route. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Antimicrobial Effects of Violacein against Planktonic Cells and Biofilms of Staphylococcus aureus
Molecules 2017, 22(10), 1534; doi:10.3390/molecules22101534
Received: 7 August 2017 / Revised: 7 September 2017 / Accepted: 9 September 2017 / Published: 25 September 2017
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Abstract
Violacein is an indole compound, produced by Chromobacterium violaceum, a bacteria present in tropical and subtropical areas. Among its numerous biological activities, its antimicrobial potential stands out. This study aims to determine the antimicrobial activity of VIO on S. aureus in planktonic
[...] Read more.
Violacein is an indole compound, produced by Chromobacterium violaceum, a bacteria present in tropical and subtropical areas. Among its numerous biological activities, its antimicrobial potential stands out. This study aims to determine the antimicrobial activity of VIO on S. aureus in planktonic culture and biofilms. VIO showed excellent antimicrobial activity in inhibiting and killing S. aureus in planktonic cultures and biofilm formation. The minimum bactericidal concentration (5 μg/mL) of VIO caused the death of S. aureus after 3–4 h of exposure and the minimum inhibitory concentration (1.25 μg/mL) of VIO inhibited bacterial growth within the first 8 h of contact. Biofilm formation was also strongly inhibited by VIO (1.25 μg/mL), in contrast to the higher resistance verified for S. aureus in mature biofilm (40 μg/mL). The high bacterial metabolic activity favored VIO activity; however, the good activity observed during phases of reduced metabolism indicates that VIO action involves more than one mechanism. Thus, VIO is a promising molecule for the development of an antimicrobial drug for the eradication of S. aureus infections. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Antibiofilm Activity and Mechanism of Action of the Disinfectant Chloramine T on Candida spp., and Its Toxicity against Human Cells
Molecules 2017, 22(9), 1527; doi:10.3390/molecules22091527
Received: 22 August 2017 / Revised: 8 September 2017 / Accepted: 9 September 2017 / Published: 17 September 2017
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Abstract
We evaluated the antifungal and anti-biofilm activity, mechanism of action and cytotoxicity of chloramine T trihydrate (CAT) against Candida spp. The Minimum Inhibitory and Fungicidal Concentrations (MIC/MFC) of CAT were determined. Changes in CAT-treated C. albicans growth kinetics and micromorphology were evaluated, as
[...] Read more.
We evaluated the antifungal and anti-biofilm activity, mechanism of action and cytotoxicity of chloramine T trihydrate (CAT) against Candida spp. The Minimum Inhibitory and Fungicidal Concentrations (MIC/MFC) of CAT were determined. Changes in CAT-treated C. albicans growth kinetics and micromorphology were evaluated, as well as the mechanism of action, and its effects on biofilm. Cytotoxicity was assessed by the hemolysis method. The data were analyzed by inferential statistics (p ≤ 0.05). CAT showed antifungal activity against all strains, with MIC values ranging between 1.38 and 5.54 mmol/L (MIC75%: 2.77 mmol/L). CAT demonstrated an immediate and sustained action on C. albicans growth kinetics, particularly at 2 × MIC. This compound likely acts on the cell wall and membrane permeability simultaneously and was found to cause changes in C. albicans micromorphology. Tha antibiofilm activity of CAT was similar to that of sodium hypochlorite (p > 0.05) against mature biofilms. CAT was more effective than NaOCl in reducing mature biofilm upon 1-min exposure at 2 × MIC (24 h) and 4 × MIC (48 h) (p < 0.05). Toxicological analysis revealed that CAT had hemolytic activity between 61 and 67.7% as compared to 100% by NaOCl. CAT has antifungal and anti-biofilm properties, probably acting on both cell wall and membrane permeability, and showed low toxicity in vitro. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters
Molecules 2017, 22(9), 1538; doi:10.3390/molecules22091538
Received: 28 August 2017 / Revised: 8 September 2017 / Accepted: 8 September 2017 / Published: 12 September 2017
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Abstract
A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures
[...] Read more.
A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures of all the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. The target compounds exhibited best antifungal activity against P. piricola, in which compounds (Z)-4r (R = β-pyridyl), (Z)-4q (R = α-thienyl), (E)-4f′ (R = p-F Ph), (Z)-4i (R = m-Me Ph), (Z)-4j (R = p-Me Ph), and (Z)-4p (R = α-furyl) had inhibition rates of 97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and 77.7%, respectively, showing better antifungal activity than that of the commercial fungicide chlorothanil. Also, compound (Z)-4r (R = β-pyridyl) displayed remarkable antifungal activity against all the tested fungi, with inhibition rates of 76.7%, 82.7%, 97.1%, 66.3%, 74.7%, 93.9%, 76.7% and 93.3%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide chlorothanil. Besides, the E-Z isomers of the target oxime esters were found to show obvious differences in antifungal activity. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids
Molecules 2017, 22(9), 1491; doi:10.3390/molecules22091491
Received: 15 August 2017 / Accepted: 5 September 2017 / Published: 7 September 2017
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Abstract
Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form,
[...] Read more.
Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL−1 (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL−1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Synthesis and Biological Activity of Novel O-Alkyl Derivatives of Naringenin and Their Oximes
Molecules 2017, 22(9), 1485; doi:10.3390/molecules22091485
Received: 13 August 2017 / Revised: 1 September 2017 / Accepted: 2 September 2017 / Published: 6 September 2017
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Abstract
O-Alkyl derivatives of naringenin (1a10a) were prepared from naringenin using the corresponding alkyl iodides and anhydrous potassium carbonate. The resulting products were used to obtain oximes (1b10b). All compounds were tested for antimicrobial activity
[...] Read more.
O-Alkyl derivatives of naringenin (1a10a) were prepared from naringenin using the corresponding alkyl iodides and anhydrous potassium carbonate. The resulting products were used to obtain oximes (1b10b). All compounds were tested for antimicrobial activity against Escherichia coli ATCC10536, Staphylococcus aureus DSM799, Candida albicans DSM1386, Alternaria alternata CBS1526, Fusarium linii KB-F1, and Aspergillus niger DSM1957. The resulting biological activity was expressed as the increase in optical density (ΔOD). The highest inhibitory effect against E. coli ATCC10536 was observed for 7,4′-di-O-pentylnaringenin (8a), 7-O-dodecylnaringenin (9a), naringenin oxime (NG-OX), 7,4′-di-O-pentylnaringenin oxime (8b), and 7-O-dodecylnaringenin oxime (9b) (ΔOD = 0). 7-O-dodecylnaringenin oxime (9b) also inhibited the growth of S. aureus DSM799 (ΔOD = 0.35) and C. albicans DSM1386 (ΔOD = 0.22). The growth of A. alternata CBS1526 was inhibited as a result of the action of 7,4′-di-O-methylnaringenin (2a), 7-O-ethylnaringenin (4a), 7,4′-di-O-ethylnaringenin (5a), 5,7,4′-tri-O-ethylnaringenin (6a), 7,4′-di-O-pentylnaringenin (8a), and 7-O-dodecylnaringenin (9a) (ΔOD in the range of 0.49–0.42) in comparison to that of the control culture (ΔOD = 1.87). In the case of F. linii KB-F1, naringenin (NG), 7,4′-di-O-dodecylnaringenin (10a), 7-O-dodecylnaringenin oxime (9b), and 7,4′-di-O-dodecylnaringenin oxime (10b) showed the strongest effect (ΔOD = 0). 7,4′-Di-O-pentylnaringenin (8a) and naringenin oxime (NG-OX) hindered the growth of A. niger DSM1957 (ΔOD = 0). Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Diarylethenes Display In Vitro Anti-TB Activity and Are Efficient Hits Targeting the Mycobacterium tuberculosis HU Protein
Molecules 2017, 22(8), 1245; doi:10.3390/molecules22081245
Received: 9 July 2017 / Accepted: 22 July 2017 / Published: 25 July 2017
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Abstract
Tuberculosis continues to be a great source of concern in global health because of the large reservoir of humans infected with the bacilli and the appearance of clinical isolates resistant to a wide array of anti-tuberculosis drugs. New drugs with novel mechanisms of
[...] Read more.
Tuberculosis continues to be a great source of concern in global health because of the large reservoir of humans infected with the bacilli and the appearance of clinical isolates resistant to a wide array of anti-tuberculosis drugs. New drugs with novel mechanisms of action on new targets are urgently required to reduce global tuberculosis burden. Mycobacterium tuberculosis nucleoid associated protein (NAP) HU has been shown to be druggable and essential for the organism’s survival. In this study, four diarylethenes were synthesized using a one-pot decarboxylated Heck-coupling of coumaric acids with iodoanisoles. The prepared compounds 14 were tested for their in vitro growth inhibition of M. tuberculosis H37Rv using the spot culture growth inhibition assay, displaying minimum inhibitory concentrations between 9 and 22 µM. Their cytotoxicity against BHK-21 cell line showed half inhibition at concentrations between 98 and 729 µM. The most selective hit (SI = 81), demonstrated inhibition of M. tuberculosis HU protein involved in maintaining bacterial genome architecture. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies
Molecules 2017, 22(6), 1015; doi:10.3390/molecules22061015
Received: 22 May 2017 / Revised: 14 June 2017 / Accepted: 15 June 2017 / Published: 18 June 2017
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Abstract
Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to
[...] Read more.
Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC50 range 15.8–26.1 μg/mL) in comparison with benznidazole and nifurtimox (LC50 range 33.1–46.7 μg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90–60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Design, Synthesis and Biological Evaluation of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides as Antiprotozoal Agents
Molecules 2017, 22(4), 579; doi:10.3390/molecules22040579
Received: 24 January 2017 / Revised: 31 March 2017 / Accepted: 31 March 2017 / Published: 4 April 2017
PDF Full-text (3051 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is
[...] Read more.
Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is considered a privileged structure in medicinal chemistry. In this study, the benzimidazole core served as a model for the synthesis of a series of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides 18 as benznidazole analogues. The in silico pharmacological results calculated with PASS platform exhibited chemical structures highly similar to known antiprotozoal drugs. Compounds 1–8 when evaluated in silico for acute toxicity by oral dosing, were less toxic than benznidazole. The synthesis of compounds 18 were carried out through reaction of 5(6)-nitro-1H-benzimidazol-2-amine (12) with 2-chlroactemides 10ah, in the presence of K2CO3 and acetonitrile as solvent, showing an inseparable mixture of two regioisomers with the -NO2 group in position 5 or 6 with chemical yields of 60 to 94%. The prediction of the NMR spectra of molecule 1 coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomer endo-1,6-NO2 predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites (Giardia intestinalis and Entamoeba histolytica) and a urogenital tract parasite (Trichomonas vaginalis) were tested. Compound 7 showed an IC50 of 3.95 μM and was 7 time more active against G. intestinalis than benznidazole. Compounds 7 and 8 showed 4 times more activity against T. vaginalis compared with benznidazole. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle (R)-(−)-Aloesaponol III 8-Methyl Ether from Eremurus persicus: A Novel Compound against Leishmaniosis
Molecules 2017, 22(4), 519; doi:10.3390/molecules22040519
Received: 15 February 2017 / Revised: 14 March 2017 / Accepted: 20 March 2017 / Published: 24 March 2017
PDF Full-text (3045 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania
[...] Read more.
Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the (R) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that (R)-ASME inhibits Leishmania infantum promastigotes viability (IC50 73 µg/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners
Molecules 2017, 22(3), 343; doi:10.3390/molecules22030343
Received: 9 January 2017 / Revised: 6 February 2017 / Accepted: 16 February 2017 / Published: 24 February 2017
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Abstract
Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth. Synthesized
[...] Read more.
Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth. Synthesized compounds were evaluated for their antimalarial activity and toxicity, in vitro and in mice. Benzothiophenes presented in this paper showed improved activities against a chloroquine susceptible (CQS) strain, with potencies of IC50 = 6 nM, and cured 5/5 Plasmodium berghei infected mice when dosed orally at 160 mg/kg/day × 3 days. In the benzothiophene series, the examined antiplasmodials were more active against the CQS strain D6, than against strains chloroquine resistant (CQR) W2 and multidrug-resistant (MDR) TM91C235. For the thiophene series, a very interesting feature was revealed: hypersensitivity to the CQR strains, resistance index (RI) of <1. This is in sharp contrast to chloroquine, indicating that further development of the series would provide us with more potent antimalarials against CQR strains. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Open AccessArticle Synthesis of 16 New Hybrids from Tetrahydropyrans Derivatives and Morita˗Baylis˗Hillman Adducts: In Vitro Screening against Leishmania donovani
Molecules 2017, 22(2), 207; doi:10.3390/molecules22020207
Received: 19 December 2016 / Accepted: 25 January 2017 / Published: 30 January 2017
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Abstract
Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala‐aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The
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Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala‐aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The Morita‐Baylis‐Hillman adducts (MBHAs) are being explored as drug candidates against several diseases, one of them being leishmaniasis. We present here the design, synthesis and in vitro screening against Leishmania donovani of sixteen new molecular hybrids from analgesic/antiinflammatory tetrahydropyrans derivatives and Morita˗Baylis˗Hillman adducts. First, acrylates were synthesized from analgesic/anti‐inflammatory tetrahydropyrans using acrylic acid under TsOH as a catalyst (70–75% yields). After the 16 new MBHAs were prepared in moderate to good yields (60–95%) promoted by microwave irradiation or low temperature (0 °C) in protic and aprotic medium. The hybrids were evaluated in vitro on the promastigote stage of Leishmania donovani by determining their inhibitory concentrations 50% (IC50), 50% hemolysis concentration (HC50), selectivity index (HC50/IC50,), and comparing to Amphotericin B, chosen as the anti‐leishmanial reference drug. The hybrid which presents the bromine atom in its chemical structure presents high leishmanicide activity and the high selectivity index in red blood cells (SIrb > 180.19), compared with the highly‐toxic reference drug (SIrb = 33.05), indicating that the bromine hybrid is a promising compound for further biological studies. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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