Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani
- Author(s)
- McNamara, N; Saunders, E; Varghese, S; Zheng, R; Simpson, K; Varma, DM; Johnson, MM; Zahid, MSH; Bachelder, EM; Ainslie, KM; No, JH; Koh, D; Shum, D; Das, N; Patra, B; Roy, J; Talukdar, A; Ganguly, D; McConville, M; Baell, J;
- Journal Title
- European Journal of Medicinal Chemistry
- Publication Type
- Research article
- Abstract
- Visceral 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.
- Publisher
- Elsevier
- Keywords
- *Antiprotozoal Agents/chemistry; Humans; Imidazoles/therapeutic use; *Leishmania donovani; *Leishmaniasis, Visceral/drug therapy; *Trypanosoma cruzi; Early hit-to-lead SAR exploration; L. donovani inhibitors; Neglected tropical disease; Phenyl imidazole carboxamides; Visceral leishmaniasis
- Department(s)
- Laboratory Research
- PubMed ID
- 35810535
- Publisher's Version
- https://doi.org/10.1016/j.ejmech.2022.114577
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-01-31 05:10:57
Last Modified: 2025-01-31 05:11:49