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.

Figure 1

Scaffold evolution of 2-(quinolin-4-yloxy)acetamides and the novel compounds designed with the aim of reducing the amide carbonyl electrophilicity, which could increase stability in hydrolysis mediated-reactions.

Scheme 1

Conditions and reagents are as follows: i = K₂CO₃ and DMF at 25 °C for 18 h. Minimum inhibitory concentration (MIC) against the M. tuberculosis H37Rv strain. INH = isoniazid. RIF = rifampin.

Scheme 2

Conditions, reagents, and reactants are as follows: i = K₂CO₃ and DMF at 25 °C for 18 h. Minimum inhibitory concentration (MIC) against the M. tuberculosis H37Rv strain.