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

Celso Yassuo Okada-Junior; Gustavo Claro Monteiro; Anna Caroline Campos Aguiar; Victor Sousa Batista; Juliana Oliveira de Souza; Guilherme Eduardo Souza; Renata Vieira Bueno; Glaucius Oliva; Nailton M Nascimento-Júnior; Rafael Victorio Carvalho Guido; Vanderlan Silva Bolzani

doi:10.1021/acsomega.8b01062

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

ACS Omega. 2018 Aug 20;3(8):9424-9430. doi: 10.1021/acsomega.8b01062. eCollection 2018 Aug 31.

Affiliations

¹ Nuclei of Bioassays, Biosynthesis and Ecophysiology of Natural Products (NuBBE), Department of Organic Chemistry, Institute of Chemistry, and Laboratory of Medicinal Chemistry, Organic Synthesis and Molecular Modeling (LaQMedSOMM), Department of Organic Chemistry, Institute of Chemistry, São Paulo State University-UNESP, Rua Professor Francisco Degni, 55, Jardim Quitandinha, 14800-060 Araraquara, São Paulo, Brazil.
² Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 Jardim Santa Angelina, Sao Carlos, São Paulo 13563-120, Brazil.

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.