1022224-85-6Relevant articles and documents
4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides
Meyers, Marvin J.,Liu, Jianguang,Xu, Jing,Leng, Fang,Guan, Jiantong,Liu, Zhijun,McNitt, Sarah A.,Qin, Limei,Dai, Linglin,Ma, Hongwei,Adah, Dickson,Zhao, Siting,Li, Xiaofen,Polino, Alex J.,Nasamu, Armiyaw S.,Goldberg, Daniel E.,Liu, Xiaorong,Lu, Yongzhi,Tu, Zhengchao,Chen, Xiaoping,Tortorella, Micky D.
, p. 3503 - 3512 (2019/03/29)
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.
