Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure-Activity Relationship Studies, and Biological Assessment.

A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron (IC NF54 = 0.81 μM) and its methyl-substituted analogue (IC NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue with high potency against the drug-sensitive NF54 (IC NF54 = 0.062 μM) and multidrug-resistant K1 (IC K1 = 0.054 μM) strains of the human malaria parasite . Compounds and gratifyingly showed in vivo efficacy in both and mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound , were identified.