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Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

Chemical Biology and Drug Design, ISSN: 1747-0285, Vol: 92, Issue: 3, Page: 1585-1596
2018
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Article Description

Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2-substituted-1H-benzo[d]imidazole derivatives (9a–d) showing affinity in the submicromolar range (K = 0.15–0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC = 6.8 μM), although with some degree of cytotoxicity (CC = 8.0 μM on PMM and CC = 32.0 μM on MCR-5). In silico molecular docking studies and ADME-Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives.

Bibliographic Details

De Luca, Laura; Ferro, Stefania; Buemi, Maria Rosa; Monforte, Anna-Maria; Gitto, Rosaria; Schirmeister, Tanja; Maes, Louis; Rescifina, Antonio; Micale, Nicola

Wiley

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Chemistry

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