Antitubercular Activity of Novel 2-(Quinoline-4-yloxy)acetamides with Improved Drug-Like Properties.
Borsoi AF, Alice LM, Sperotto N, Ramos AS, Abbadi BL, Macchi Hopf FS, Silva Dadda AD, Rambo RS, Madeira Silva RB, Paz JD, Pissinate K, Muniz MN, Neves CE, Galina L, González LC, Perelló MA, de Matos Czeczot A, Leyser M, de Oliveira SD, de Araújo Lock G, de Araújo BV, Costa TD, Bizarro CV, Basso LA, Machado P.
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 <i>in vitro</i> inhibitors of <i>Mycobacterium tuberculosis</i> (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 <i>qcrB</i> mutant strain indicated that the structures targeted the cytochrome <i>bc</i> <sub>1</sub> 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 <i>in vitro</i> 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 <i>in vivo</i> effectiveness and its further development as an antituberculosis drug candidate.