Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors.

ABSTRACT: A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino-pyrimidinone-fused pyrrolidine (IPF) scaffold that exhibited sub-micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related aspartic protease plasmepsin X showed inhibitory activity, while a third aspartic protease, plasmepsin IX, was not significantly inhibited. Modifications to the P1 biaryl region of the IPF scaffold differentially modulated inhibition of both plasmepsin V and X. Notably, analogs with potent plasmepsin X inhibitory activity successfully blocked the growth of Plasmodium falciparum in vitro. X-ray structures of IPF analogs in complex with plasmepsin V

SUBMITTER: Hodder AN 

PROVIDER: S-EPMC12138161 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature