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ACS Med Chem Lett. 2019 May 28;10(6):966-971. doi: 10.1021/acsmedchemlett.9b00123. eCollection 2019 Jun 13.

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

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Department of Chemistry, Saint Louis University, Saint Louis, Missouri 63103, United States.
Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
Laboratory of Pathogen Biology, State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Legion Pharma Co Ltd., Guangzhou 510530, China.


Malaria is caused by infection from the Plasmodium parasite and kills hundreds of thousands of people every year. Emergence of new drug resistant strains of Plasmodium demands identification of new drugs with novel chemotypes and mechanisms of action. As a follow up to our evaluation of 4-aryl-N-benzylpyrrolidine-3-carboxamides as novel pyrrolidine-based antimalarial agents, we describe herein the structure-activity relationships of the reversed amide homologues 2-aryl-N-(4-arylpyrrolidin-3-yl)acetamides. Unlike their carboxamide homologues, acetamide pyrrolidines do not require a third chiral center to be potent inhibitors of P. falciparum and have good pharmacokinetic properties and improved oral efficacy in a mouse model of malaria. Compound (-)-32a (CWHM-1552) has an in vitro IC50 of 51 nM in the P. falciparum 3D7 assay and an in vivo ED90 of <10 mg/kg/day and ED99 of 30 mg/kg/day in a murine P. chabaudi model. Remarkably, the absolute stereochemical preference for this acetamide series (3S,4R) 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.

[Available on 2020-06-13]

Conflict of interest statement

The authors declare the following competing financial interest(s): X.C., L.D., J.L., H.M., M.D.T., and M.J.M. are inventors on a patent application filed by Legion Pharma claiming compounds in this manuscript. M.D.T. owns stock in Legion Pharma.

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