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

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.

Exploring Scaffold Hopping for Novel 2-(Quinolin-4-yloxy)acetamides with Enhanced Antimycobacterial Activity

“…Indeed, telacebec yielded an MIC in nanomolar range presenting value of 0.009 μM under the evaluated experimental conditions. Conversely, when compared to 2-(quinolin-4yloxy)acetamide 3 (INCT-TB1164), 16 these molecules were 4.5-fold more potent. Lastly, the comparison of the MIC values of the structures 8a−c, 8j with the first-line drugs showed the most significant differences.…”

“…In contrast, 2-(quinolin-4-yloxy)acetamide 3, when tested under similar conditions, exhibited reduction of 0.97 log 10 CFU. 16 This result suggests a superior capacity of these new molecules to prevent the intracellular growth of the bacillus.…”

“…However, for prioritization purposes, compounds 8b−c, 8j demonstrated greater stability regardless of the condition to which they were exposed. It is important to highlight that the concentration of 2-(quinolin-4-yloxy)acetamide 3 is reduced by approximately 40% when exposed to pH 1.2 and 9.1 for 24 h. 16 The subsequent test assessed the solubility of the compounds at two key pH levels experienced by a drug in the biophase. The data indicated that solubility in acidic pH of the methoxylated molecules 8a and 8j was significantly lower than that of the halogenated structures 8b and 8c.…”

“…14−16 This chemical class was discovered by GSK from phenotypic assays 17 and our research efforts have resulted in optimized compounds, including the most promising structure in the 2-(quinolin-4-yloxy)acetamide class reported to date, INCT-TB1164 (Figure 1). 16 Importantly, studies using targeted or whole genome sequencing of selected spontaneous mutants have inferred that bc 1 complex is related with antimycobacterial activity elicited by 2-(quinolin-4-yloxy)acetamides. 18,19 Hence, the aim of this study was to employ the scaffold hopping approach to develop novel 2-(quinolin-4-yloxy)-acetamides with antimycobacterial properties.…”

“…Our hypothesis suggests that this dramatic reduction in antimicrobial activity may be attributed to the challenge of protonating the quinolinic ring in the presence of chemical groups that decrease the electronic density of the heterocycle. 16 This protonation difficulty could potentially affect intermolecular interactions with the molecular target of the structures, thus diminishing their inhibitory activities against Mtb.…”