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European Journal of Medicinal Chemistry Dec 2020Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of...
Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.
Topics: Anti-Bacterial Agents; Antiprotozoal Agents; Catalysis; Chemistry Techniques, Synthetic; Mycobacterium smegmatis; Palladium; Plasmodium falciparum; Quinones; Trypanosoma brucei rhodesiense
PubMed: 33002847
DOI: 10.1016/j.ejmech.2020.112837 -
The Biochemical Journal Sep 2011New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and... (Review)
Review
New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies.
Topics: Animals; Antiprotozoal Agents; Homeostasis; Host-Pathogen Interactions; Humans; Parasites; Polyamines
PubMed: 21834794
DOI: 10.1042/BJ20110362 -
Biochimie Oct 2021Leishmaniasis is a neglected parasitic disease for which the conventional treatment can be considered inefficient and extremely aggressive, generating several and severe...
Leishmaniasis is a neglected parasitic disease for which the conventional treatment can be considered inefficient and extremely aggressive, generating several and severe side effects. Therefore, the discovery of new drug candidates is important for the improvement in the quality of life of patients. Previously, we reported the promising results of isopentyl caffeate (ICaf) against Leishmania chagasi (agent of visceral leishmaniasis) and Leishmania amazonensis (agent of cutaneous leishmaniasis) promastigotes, displaying IC of 1.56 and 1.71 μM, respectively. Herein, we aimed to decipher the mechanisms of anti-Leishmania action of ICaf. Light and scanning electron microscopy assays showed relevant morphological changes in promastigotes when treated with ICaf, including rounding of the parasite body, shortening of the flagellum, blebs on the plasma membrane and cellular aggregation. The parasite mitochondrion was targeted by ICaf, resulting in a significant reduction in its metabolic activity and electric membrane potential followed by an increase in the production of reactive oxygen species, which culminated in the loss of plasma membrane integrity and parasite death. Relevantly, ICaf also had a potent anti-amastigote action. The IC values calculated for intracellular amastigotes of L. amazonensis were 3.27, 1.60 and 1.52 μM, while for L. chagasi the values were 2.48, 1.84 and 1.60 μM, respectively, after treating the infected macrophages with ICaf for 24, 48 and 72 h. ICaf was well tolerated by THP-1 macrophages, which gave rise to excellent selectivity indexes considering both Leishmania species. The current results suggest that ICaf may emerge as a chemotherapeutic alternative for the treatment of leishmaniasis.
Topics: Antiprotozoal Agents; Caffeic Acids; Humans; Leishmania infantum; Leishmaniasis, Visceral; Macrophages; THP-1 Cells
PubMed: 34216704
DOI: 10.1016/j.biochi.2021.06.015 -
International Journal of Antimicrobial... Aug 2022A growing number of studies have demonstrated the in vitro potential of an impressive number of antileishmanial candidates in the past years. However, the lack of... (Review)
Review
A growing number of studies have demonstrated the in vitro potential of an impressive number of antileishmanial candidates in the past years. However, the lack of uniformity regarding the choice of cell types for cytotoxicity assays may lead to uncomparable and inconclusive data. In vitro assays relying solely on non-phagocytic cell models may not represent a realistic result as the effect of an antileishmanial agent should ideally be presented based on its cytotoxicity profile against reticuloendothelial system cells. In the present review, we have assembled studies published in the scientific literature from 2015 to 2021 that explored leishmanicidal candidates, emphasising the main host cell models used for cytotoxicity assays. The pros and cons of different host cell types as well as primary cells and cell lines are discussed in order to draw attention to the need to establish standardised protocols for preclinical testing when assessing new antileishmanial candidates.
Topics: Antiprotozoal Agents; Cell Line
PubMed: 35691601
DOI: 10.1016/j.ijantimicag.2022.106612 -
Journal of Enzyme Inhibition and... Dec 2020A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and...
Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives.
A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated against three protozoan parasites (, , and ). Biological results showed antiprotozoal activity with IC values in the µM range. In addition, the cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the CQ-sensitive strain 3D7. The quinazoline was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on strain. Moreover, as the telomeres of the parasites and are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the and telomeric G-quadruplexes by our best compounds through FRET melting assays.
Topics: Antiprotozoal Agents; Drug Design; Hep G2 Cells; Humans; Leishmania donovani; Plasmodium falciparum; Quinolines; Structure-Activity Relationship; Trypanosoma brucei brucei
PubMed: 31899980
DOI: 10.1080/14756366.2019.1706502 -
Molecules (Basel, Switzerland) Jan 2022Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little... (Review)
Review
Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.
Topics: Animals; Antiprotozoal Agents; Chemistry Techniques, Synthetic; Drug Development; Humans; Indoles; Leishmania; Leishmaniasis; Malaria; Parasitic Sensitivity Tests; Plasmodium; Structure-Activity Relationship; Trypanosoma; Trypanosomiasis
PubMed: 35011552
DOI: 10.3390/molecules27010319 -
Frontiers in Cellular and Infection... 2022Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include...
Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1-12) and evaluated their inhibitory efficacy against the AG83 strain of . Among the synthesized glycosides, the inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure-activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote-macrophage infection model as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL.
Topics: Amphotericin B; Antiprotozoal Agents; Glycosides; Humans; Leishmania donovani; Leishmaniasis, Visceral; Metalloproteases
PubMed: 35601095
DOI: 10.3389/fcimb.2022.803048 -
Parasitology Apr 2022Cutaneous leishmaniasis (CL) is a spectrum of clinical manifestations characterized by severe skin ulcerations that leads to social stigma. There are limited treatment...
Cutaneous leishmaniasis (CL) is a spectrum of clinical manifestations characterized by severe skin ulcerations that leads to social stigma. There are limited treatment options for CL, and the available drugs are becoming less efficacious due to drug resistance. More efficacious and safer antileishmanial drugs are needed. In this study, the biological effect of seven synthetically accessible nitroaromatic compounds was evaluated in vitro against amastigotes of Leishmania amazonensis, followed by in vivo evaluation using mouse models of CL. Two compounds (6 and 7) were active against amastigotes in vitro [half-maximal effective concentration (EC50): 4.57 ± 0.08 and 9.19 ± 0.68 μm, respectively], with selectivity indexes >50, and the other compounds were not selective. In vivo, compounds 6 and 7 (10 mg kg−1, twice a day for 14 days) failed to reduce skin lesion sizes and parasite loads determined by light microscopy of lesion imprints and quantitative polymerase chain reaction. Nevertheless, the in vitro leishmanicidal efficacy sustained their use as templates for nitroimidazole-based antileishmanial drug discovery programmes focusing on analogues with more suitable properties.
Topics: Animals; Antiprotozoal Agents; Leishmania mexicana; Leishmaniasis, Cutaneous; Mice; Mice, Inbred BALB C; Nitro Compounds
PubMed: 35109958
DOI: 10.1017/S0031182021002079 -
FEMS Immunology and Medical Microbiology Feb 2010Trypanosomiases and Leishmaniases are neglected tropical diseases that affect the less developed countries. For this reason, they did not and still do not have high... (Review)
Review
Trypanosomiases and Leishmaniases are neglected tropical diseases that affect the less developed countries. For this reason, they did not and still do not have high visibility in Western societies. The name neglected diseases also refers to the fact that they often received little interest at the level of public investment, research and development. The drug discovery scenario, however, is changing dramatically. After a period in which different socioeconomic factors have prevented massive research efforts in this field, such efforts have increased considerably in the very recent years, with significant scientific advancements. In this context, we have embarked on a new drug discovery project devoted to identification of new small molecules for the treatment of trypanosomal and leishmanial diseases. Two complementary approaches have been pursued and are reported here. The first deals with a structure-based drug design, and a privileged structure-guided synthesis of quinazoline compounds able to modulate trypanothione reductase activity was accomplished. In the second, a combinatorial library, built on a natural product-based strategy, was synthesized. Using whole parasite assays, different quinones have been identified as promising lead compounds. A combination of both approaches to hopefully overcome some of the challenges of anti-trypanosomatid drug discovery has eventually been proposed.
Topics: Animals; Antiprotozoal Agents; Chemistry, Pharmaceutical; Combinatorial Chemistry Techniques; Drug Design; Drug Discovery; Humans; Leishmania; Leishmaniasis; Quinazolines; Trypanocidal Agents; Trypanosoma; Trypanosomiasis
PubMed: 19845762
DOI: 10.1111/j.1574-695X.2009.00615.x -
PLoS Neglected Tropical Diseases Dec 2014The discovery of new therapeutic options against Trypanosoma cruzi, the causative agent of Chagas disease, stands as a fundamental need. Currently, there are only two... (Review)
Review
The discovery of new therapeutic options against Trypanosoma cruzi, the causative agent of Chagas disease, stands as a fundamental need. Currently, there are only two drugs available to treat this neglected disease, which represents a major public health problem in Latin America. Both available therapies, benznidazole and nifurtimox, have significant toxic side effects and their efficacy against the life-threatening symptomatic chronic stage of the disease is variable. Thus, there is an urgent need for new, improved anti-T. cruzi drugs. With the objective to reliably accelerate the drug discovery process against Chagas disease, several advances have been made in the last few years. Availability of engineered reporter gene expressing parasites triggered the development of phenotypic in vitro assays suitable for high throughput screening (HTS) as well as the establishment of new in vivo protocols that allow faster experimental outcomes. Recently, automated high content microscopy approaches have also been used to identify new parasitic inhibitors. These in vitro and in vivo early drug discovery approaches, which hopefully will contribute to bring better anti-T. cruzi drug entities in the near future, are reviewed here.
Topics: Animals; Antiprotozoal Agents; Chagas Disease; DNA, Protozoan; Drug Discovery; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Mice; Trypanosoma cruzi
PubMed: 25474364
DOI: 10.1371/journal.pntd.0003259