Phthalimide Derivatives with Bioactivity against Plasmodium falciparum: Synthesis, Evaluation, and Computational Studies Involving bc ₁ Cytochrome Inhibition.

ABSTRACT: We describe herein the design and synthesis of N-phenyl phthalimide derivatives with inhibitory activities against Plasmodium falciparum (sensitive and resistant strains) in the low micromolar range and noticeable selectivity indices against human cells. The best inhibitor, 4-amino-2-(4-methoxyphenyl)isoindoline-1,3-dione (10), showed a slow-acting mechanism similar to that of atovaquone. Enzymatic assay indicated that 10 inhibited P. falciparum cytochrome bc ₁ complex. Molecular docking studies suggested the binding mode of the best hit to Qo site of the cytochrome bc ₁ complex. Our findings suggest that 10 is a promising candidate for hit-to-lead development.

SUBMITTER: Okada-Junior CY 

PROVIDER: S-EPMC6644792 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature