Benzimidazole derivatives as antimalarial agents: Design, Synthesis and Structure-Activity relationship studies

Malaria is still one of the leading cause of morbidity and mortality in the human history. With over 90% of the world’s malaria mortality attributed to Plasmodium falciparum, this parasite remains a major global health threat, highlighting the need for increased efforts in antimalarial drug discovery. This study aims to develop next-generation treatment options to combat malaria. We screened in-house library of compounds and identified HIPS709 as an initial hit with IC₅₀ of 470 nM against Plasmodium falciparum NF54. After two rounds of Structure-Activity Relationship (SAR) optimization, we successfully identified four compounds with significantly improved activity profiles. Among these, the most promising compound exhibited an impressive ~25 fold increase in activity. The front-runner compounds were subjected to in vitro ADMET profiling while mode of action studies are currently in progress.