Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum

• Published in: Bioorganic & medicinal chemistry letters 2017-06, Vol.27 (11), p.2459-2464
• Main Authors: Gomes, Marcelo N., Alcântara, Laura M., Neves, Bruno J., Melo-Filho, Cleber C., Freitas-Junior, Lucio H., Moraes, Carolina B., Ma, Rui, Franzblau, Scott G., Muratov, Eugene, Andrade, Carolina Horta
• Format: Article
• Language: English
• Subjects: Amphotericin B - pharmacology; Animals; Antileishmanial agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Chlorocebus aethiops; Computer Simulation; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Databases, Factual; Drug Discovery; Humans; Leishmania infantum - drug effects; Molecular Docking Simulation; Molecular modeling; Nitrofurans - chemical synthesis; Nitrofurans - chemistry; Nitrofurans - pharmacology; Nitroheterocycle chalcones; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Selectivity; Structure-Activity Relationship; Target fishing; Vero Cells
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.04.010

[Display omitted] •Molecular modeling helped to prioritize compounds with potential anti-leishmanial activity.•Two chalcones-like compounds have shown high antileishmanial activity and selectivity.•SAR rules useful for molecular design were derived.•Cysteine proteases are the potential target for discovered compounds. Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2–10.98μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50μM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.