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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

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

Okada-Junior Celso Yassuo CY   Monteiro Gustavo Claro GC   Aguiar Anna Caroline Campos ACC   Batista Victor Sousa VS   de Souza Juliana Oliveira JO   Souza Guilherme Eduardo GE   Bueno Renata Vieira RV   Oliva Glaucius G   Nascimento-Júnior Nailton M NM   Guido Rafael Victorio Carvalho RVC   Bolzani Vanderlan Silva VS  

ACS omega 20180820 8

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>b  ...[more]

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