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J Med Chem. 2019 Apr 11;62(7):3503-3512. doi: 10.1021/acs.jmedchem.8b01972. Epub 2019 Mar 22.

4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides.

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Department of Chemistry , Saint Louis University , Saint Louis , Missouri 63103 , United States.
Center for World Health and Medicine , Saint Louis University School of Medicine , Saint Louis , Missouri 63104 , 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.
Departments of Medicine and Molecular Microbiology , Washington University in St. Louis , Saint Louis , Missouri 63110 , United States.
Legion/Lijien Pharmaceuticals , Guangzhou 510530 , China.


Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases. Extensive profiling of the two terminal aryl rings revealed a structure-activity relationship in which relatively few substituents are tolerated at the benzylic position, but the 3-aryl position tolerates a range of hydrophobic groups and some heterocycles. Out of this effort, we identified (+)-54b (CWHM-1008) as a lead compound. 54b has EC50 values of 46 and 21 nM against drug-sensitive Plasmodium falciparum 3D7 and drug-resistant Dd2 strains, respectively. Furthermore, 54b has a long half-life in mice (4.4 h) and is orally efficacious in a mouse model of malaria (qd; ED99 ∼ 30 mg/kg/day). Thus, the 4-aryl- N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.

[Available on 2020-04-11]

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