ABSTRACT
The enzyme glycerol-3-phosphate dehydrogenase (G3PDH) from Leishmania species is considered as an attractive target to design new antileishmanial drugs and a previous in silico study reported on the importance of chalcones to achieve its inhibition. Here, we report the identification of a synthetic chalcone in our in vitro assays with promastigote cells from Leishmania amazonensis, its biological activity in animal models, and docking followed by molecular dynamics simulation to investigate the molecular interactions and structural patterns that are crucial to achieve the inhibition complex between this compound and G3PDH. A molecular fragment of this natural product derivative can provide new inhibitors with increased potency and selectivity.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Glycerolphosphate Dehydrogenase/antagonists & inhibitors , Leishmania/enzymology , Animals , Glycerolphosphate Dehydrogenase/metabolism , Leishmania/drug effects , Leishmaniasis/drug therapy , Leishmaniasis/parasitology , Macrophages/drug effects , Mice , Molecular Docking SimulationABSTRACT
A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.
Subject(s)
Antiprotozoal Agents/pharmacology , Benzoxazoles/pharmacology , Leishmania mexicana/drug effects , Life Cycle Stages/drug effects , Oxadiazoles/pharmacology , Amphotericin B/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Hydrogen-Ion Concentration , Leishmania mexicana/growth & development , Life Cycle Stages/physiology , Macrophages/drug effects , Macrophages/parasitology , Male , Mice , Nitric Oxide/biosynthesis , Nitrites/metabolism , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Parasitic Sensitivity Tests , Pentamidine/pharmacology , Structure-Activity RelationshipABSTRACT
The use of indigenous or remote popular knowledge to identify new drugs against diseases or infections is a well-known approach in medicine. The inhabitants of coastal regions are known to prepare algae extracts for the treatment of disorders and ailments such as wounds, fever and stomach aches, as for the prevention of arrhythmia. Recent trends in drug research from natural sources have indicated that marine algae are a promising source of novel biochemically active compounds, especially with antiprotozoal activity. Algae survive in a competitive environment and, therefore, developed defense strategies that have resulted in a significant level of chemical structural diversity in various metabolic pathways. The exploration of these organisms for pharmaceutical and medical purposes has provided important chemical candidates for the discovery of new agents against neglected tropical diseases, stimulating the use of sophisticated physical techniques. This current review describes the main substances biosynthesized by benthic marine algae with activity against Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei; the causative agents of leishmaniasis, Chagas disease and African trypanosomiasis, respectively. Emphasis is given to secondary metabolites and crude extracts prepared from marine algae.
