Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani

Eur J Med Chem. 2022 Jul 1;240:114577. doi: 10.1016/j.ejmech.2022.114577. Online ahead of print.ABSTRACTVisceral leishmaniasis is a potentially fatal disease caused by the parasitic protists, Leishmania donovani and L. infantum. Current treatments remain unsuitable due to cost, the need for hospitalization, variable efficacy against different species, toxicity and emerging resistance. Herein, we report the SAR exploration of the novel hit 4-Fluoro-N-(5-(4-methoxyphenyl)-1-methyl-1H-imidazole-2-yl)benzamide [1] previously identified from a high throughput screen against Trypanosoma brucei, Trypanosoma cruzi and Leishmania donovani. An extensive and informative set of analogues were synthesized incorporating key modifications around the scaffold resulting in improved potency, whilst the majority of compounds maintained low cytotoxicity against human THP-1 macrophages that are target cells for these pathogens. New lead compounds identified within this study also maintained desirable physicochemical properties, improved metabolic stability in vitro and displayed no significant mitotoxicity against HepG2 cell lines. This compound class warrants continued investigation towards development as a novel treatment for Visceral Leishmaniasis.PMID:35810535 | DOI:10.1016/j.ejmech.2022.114577

Source: European Journal of Medicinal Chemistry - July 10, 2022 Category: Chemistry Authors: Nicole McNamara Eleanor Saunders Swapna Varghese Rebecca Zheng Kaylene Simpson Devika M Varma Monica M Johnson M Shamim Hasan Zahid Eric M Bachelder Kristy M Ainslie Joo Hwan No Dahae Koh David Shum Nirmal Das Binita Patra Jayasree Roy Arindam Talukdar Di Source Type: research