Quinolinyl Oxy Acettoamide Derivatives As Ant-TB Compounds 2016

2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Kenia Pissinate^†, Anne Drumond Villela^†‡, Valnês Rodrigues-Junior^†§, Bruno Couto Giacobbo^†§, Estêvão Silveira Grams^†, Bruno Lopes Abbadi^†§, Rogério Valim Trindade^†§, Laura Roesler Nery^∥, Carla Denise Bonan^§∥, Davi Fernando Back^⊥, Maria Martha Campos^†‡§, Luiz Augusto Basso^†‡§, Diógenes Santiago Santos^*†§, and Pablo Machado^*†§

^† Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^‡ Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^§ Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^∥ Laboratório de Neuroquímica e Psicofarmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^⊥ Departamento de Química, Laboratório de Materiais Inorgânicos, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil

ACS Med. Chem. Lett., 2016, 7 (3), pp 235–239

DOI: 10.1021/acsmedchemlett.5b00324

Publication Date (Web): January 11, 2016

Copyright © 2016 American Chemical Society

*Phone/Fax: +55 51 3320 3629. E-mail: diogenes@pucrs.br., *Phone/Fax: +55 51 3320 3629. E-mail: pablo.machado@pucrs.br.

Abstract

2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC₅₀s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug–drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.

Keywords:

drug-resistant research; quinoline-based compounds; SAR; Tuberculosis

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.5b00324.

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