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Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani
Nicole McNamara1, Eleanor Saunders2, Swapna Varghese1
1Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
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.
Insights
Researchers explored new drug candidates for visceral leishmaniasis, a fatal parasitic disease. Novel imidazole benzamide derivatives showed improved potency and safety, offering promise for future treatments.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Visceral leishmaniasis is a severe, fatal parasitic disease caused by Leishmania donovani and Leishmania infantum.
- Current treatments for visceral leishmaniasis are limited by cost, toxicity, variable efficacy, and emerging drug resistance.
Purpose of the Study:
- To explore the structure-activity relationship (SAR) of a novel benzamide scaffold targeting Leishmania parasites.
- To identify new lead compounds with improved potency and favorable safety profiles for visceral leishmaniasis treatment.
Main Methods:
- Synthesis and SAR exploration of novel benzamide analogues based on a previously identified hit compound.
- Evaluation of compound potency against Leishmania parasites.
- Assessment of cytotoxicity against human THP-1 macrophages and HepG2 cell lines.
- In vitro assessment of metabolic stability and physicochemical properties.
Main Results:
- Extensive SAR exploration yielded analogues with significantly improved antileishmanial potency.
- The majority of synthesized compounds exhibited low cytotoxicity against human macrophages.
- New lead compounds demonstrated desirable physicochemical properties and enhanced in vitro metabolic stability.
- No significant mitotoxicity was observed in HepG2 cell lines.
Conclusions:
- The novel benzamide derivatives represent promising lead compounds for the development of new visceral leishmaniasis treatments.
- Continued investigation into this compound class is warranted due to their improved potency, safety, and drug-like properties.
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