4-Aryl Pyrrolidines as Novel Orally Efficacious Antimalarial Agents. Part 2: 2-Aryl-N-(4-arylpyrrolidin-3-yl)acetamides

Malaria is caused by infection from the parasite and kills hundreds of thousands of people every year. Emergence of new drug resistant strains of demands identification of new drugs with novel chemotypes and mechanisms of action. As a follow up to our evaluation of 4-aryl--benzylpyrrolidine-3-carboxamides as novel pyrrolidine-based antimalarial agents, we describe herein the structure-activity relationships of the reversed amide homologues 2-aryl--(4-arylpyrrolidin-3-yl)acetamides. Unlike their carboxamide homologues, acetamide pyrrolidines do not require a third chiral center to be potent inhibitors of . and have good pharmacokinetic properties and improved oral efficacy in a mouse model of malaria. Compound (CWHM-1552) has an IC of 51 nM in the 3D7 assay and an ED of <10 mg/kg/day and ED of 30 mg/kg/day in a murine model. Remarkably, the absolute stereochemical preference for this acetamide series (3,4) is opposite of that determined for the homologous carboxamide series. Lead compounds for this class have modest affinities for the hERG channel and inhibit CYP 3A4. Additional optimization is needed in order to eliminate these undesired properties from this otherwise promising series of antimalarial compounds.