Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation.

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of MtInhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-aminoquinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-resistant tuberculosis treatments. Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Citation

Josiane Delgado Paz, Nathalia Denise de Moura Sperotto, Alessandro Silva Ramos, Kenia Pissinate, Valnês da Silva Rodrigues Junior, Bruno Lopes Abbadi, Ana Flávia Borsoi, Raoní Scheibler Rambo, Ana Carolina Corso Minotto, Adilio da Silva Dadda, Luiza Galina, Fernanda Souza Macchi Hopf, Mauro Neves Muniz, Leonardo Kras Borges Martinelli, Candida Deves Roth, Rodrigo Braccini Madeira Silva, Marcia Alberton Perelló, Alexia de Matos Czeczot, Christiano Ev Neves, Lovaine Silva Duarte, Mariana Leyser, Sílvia Dias de Oliveira, Cristiano Valim Bizarro, Pablo Machado, Luiz Augusto Basso. Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation. European journal of medicinal chemistry. 2023 Jan 05;245(Pt 1):114908

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PMID: 36435016

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