Phthalimide Derivatives with Bioactivity against <i>Plasmodium falciparum</i>: Synthesis, Evaluation, and Computational Studies Involving <i>bc</i>₁ Cytochrome Inhibition

Abstract

We describe herein the design and synthesis of <i>N</i>-phenyl phthalimide derivatives with inhibitory activities against <i>Plasmodium falciparum</i> (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 (<b>10</b>), showed a slow-acting mechanism similar to that of atovaquone. Enzymatic assay indicated that <b>10</b> inhibited <i>P. falciparum</i> cytochrome <i>bc</i> ₁ complex. Molecular docking studies suggested the binding mode of the best hit to Qo site of the cytochrome <i>bc</i> ₁ complex. Our findings suggest that <b>10</b> is a promising candidate for hit-to-lead development.