ACS medicinal chemistry letters · 2022
Antitubercular Activity of Novel 2-(Quinoline-4-yloxy)acetamides with Improved Drug-Like Properties.
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Borsoi Ana Flávia, Alice Laura Manzoli, Sperotto Nathalia, Ramos Alessandro Silva, Abbadi Bruno Lopes, Macchi Hopf Fernanda Souza, Silva Dadda Adilio da, Rambo Raoní S, Madeira Silva Rodrigo Braccini, Paz Josiane Delgado, Pissinate Kenia, Muniz Mauro Neves, Neves Christiano Ev, Galina Luiza, González Laura Calle, Perelló Marcia Alberton, de Matos Czeczot Alexia, Leyser Mariana, de Oliveira Sílvia Dias, de Araújo Lock Graziela, de Araújo Bibiana Verlindo, Costa Teresa Dalla, Bizarro Cristiano Valim, Basso Luiz Augusto, Machado Pablo
Аннотация
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.