Antitubercular Activity of Novel 2-(Quinoline-4-yloxy)acetamides with Improved Drug-Like Properties

Ana Flávia Borsoi; Laura Manzoli Alice; Nathalia Sperotto; Alessandro Silva Ramos; Bruno Lopes Abbadi; Fernanda Souza Macchi Hopf; Adilio da Silva Dadda; Raoní S Rambo; Rodrigo Braccini Madeira Silva; Josiane Delgado Paz; Kenia Pissinate; Mauro Neves Muniz; Christiano Ev Neves; Luiza Galina; Laura Calle González; Marcia Alberton Perelló; Alexia de Matos Czeczot; Mariana Leyser; Sílvia Dias de Oliveira; Graziela de Araújo Lock; Bibiana Verlindo de Araújo; Teresa Dalla Costa; Cristiano Valim Bizarro; Luiz Augusto Basso; Pablo Machado

doi:10.1021/acsmedchemlett.2c00254

Antitubercular Activity of Novel 2-(Quinoline-4-yloxy)acetamides with Improved Drug-Like Properties

ACS Med Chem Lett. 2022 Jul 21;13(8):1337-1344. doi: 10.1021/acsmedchemlett.2c00254. eCollection 2022 Aug 11.

Authors

Ana Flávia Borsoi^{1

2}, Laura Manzoli Alice¹, Nathalia Sperotto¹, Alessandro Silva Ramos¹, Bruno Lopes Abbadi¹, Fernanda Souza Macchi Hopf^{1

3}, Adilio da Silva Dadda¹, Raoní S Rambo¹, Rodrigo Braccini Madeira Silva¹, Josiane Delgado Paz^{1

3}, Kenia Pissinate¹, Mauro Neves Muniz¹, Christiano Ev Neves^{1

3}, Luiza Galina¹, Laura Calle González^{1

3}, Marcia Alberton Perelló¹, Alexia de Matos Czeczot^{1

3}, Mariana Leyser⁴, Sílvia Dias de Oliveira^{3

4}, Graziela de Araújo Lock⁵, Bibiana Verlindo de Araújo⁵, Teresa Dalla Costa⁵, Cristiano Valim Bizarro^{1

3}, Luiz Augusto Basso^{1

2

3}, Pablo Machado^{1

2

3}

Affiliations

¹ Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90616-900, Brazil.
² Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90616-900, Brazil.
³ Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90616-900, Brazil.
⁴ Laboratório de Imunologia e Microbiologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90616-900, Brazil.
⁵ Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90010-150, Brazil.

Abstract

Using cycloalkyl and electron-donating groups to decrease the carbonyl electrophilicity, a novel series of 2-(quinoline-4-yloxy)acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure-activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted the cytochrome bc ₁ complex. In addition, selected molecules inhibited Mtb growth in a macrophage model of tuberculosis infection. Furthermore, the leading compound was chemically stable depending on the context and showed good kinetic solubility, high permeability, and a low rate of in vitro metabolism. Finally, the pharmacokinetic profile of the compound was assessed after oral administration to mice. To the best of our knowledge, for the first time, a 2-(quinoline-4-yloxy)acetamide was obtained with a sufficient exposure, which may enable in vivo effectiveness and its further development as an antituberculosis drug candidate.