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

  • J Med Chem. 2019 Apr 11;62(7):3503-3512. doi: 10.1021/acs.jmedchem.8b01972.
Marvin J Meyers  1  2 ,  Jianguang Liu  3 ,  Jing Xu  3 ,  Fang Leng  3 ,  Jiantong Guan  3 ,  Zhijun Liu  3 ,  Sarah A McNitt  1  2 ,  Limei Qin  4 ,  Linglin Dai  4 ,  Hongwei Ma  3 ,  Dickson Adah  4  5 ,  Siting Zhao  4 ,  Xiaofen Li  4 ,  Alex J Polino  6 ,  Armiyaw S Nasamu  6 ,  Daniel E Goldberg  6 ,  Xiaorong Liu  3 ,  Yongzhi Lu  3 ,  Zhengchao Tu  3 ,  Xiaoping Chen  4 ,  Micky D Tortorella  3  7
Affiliations
  • 1. Department of Chemistry , Saint Louis University , Saint Louis , Missouri 63103 , United States.
  • 2. Center for World Health and Medicine , Saint Louis University School of Medicine , Saint Louis , Missouri 63104 , United States.
  • 3. Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530 , China.
  • 4. 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.
  • 5. University of Chinese Academy of Sciences , Beijing 100049 , China.
  • 6. Departments of Medicine and Molecular Microbiology , Washington University in St. Louis , Saint Louis , Missouri 63110 , United States.
  • 7. Legion/Lijien Pharmaceuticals , Guangzhou 510530 , China.
PMID: 30856324 DOI: 10.1021/acs.jmedchem.8b01972
Abstract

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.

Products