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

Marvin J. Meyers, Jianguang Liu, Jing Xu, Fang Leng, Jiantong Guan, Zhijun Liu, Sarah A. McNitt, Limei Qin, Linglin Dai, Hongwei Ma, Dickson Adah, Siting Zhao, Xiaofen Li, Alex J. Polino, Armiyaw S. Nasamu, Daniel E. Goldberg, Xiaorong Liu, Yongzhi Lu, Zhengchao Tu, Xiaoping ChenMicky D. Tortorella

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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 EC 50 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; ED 99 ∼ 30 mg/kg/day). Thus, the 4-aryl-N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.

Original languageEnglish
Pages (from-to)3503-3512
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number7
StatePublished - Apr 11 2019
Externally publishedYes

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