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

2022; American Chemical Society; Volume: 13; Issue: 8 Linguagem: Inglês

10.1021/acsmedchemlett.2c00254

1948-5875

Ana Flávia Borsoi, Laura Manzoli Alice, Nathalia Sperotto, Alessandro Silva Ramos, Bruno Lopes Abbadi, Fernanda Souza Macchi Hopf, Adílio da Silva Dadda, Raoní Scheibler 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, Sı́lvia Dias de Oliveira, Graziela de Araújo Lock, Bibiana Verlindo de Araújo, Teresa Dalla Costa, Cristiano Valim Bizarro, Luiz Augusto Basso, Pablo Machado,

Synthesis and biological activity

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 bc1 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.