QSAR-Guided Study for the Microwave-Assisted Synthesis of 4-Methylquinoline Derivatives with Antimycobacterial Activity

Tuberculosis was discovered more than a century ago, and it is still a disease that presents difficulties in its treatment due to the appearance of new resistant strains. To design new antituberculosis agents with a quinoline structure, our group developed three-dimensional structure-activity relationship (3D-QSAR) models, based on Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). Statistically robust models (q²>0.6; r²_ncv>0.8; r²_pred>0.7) and with good external predictability were obtained. We found that positions 2, 3, and 4 of the quinoline nucleus are directly related to the modulation of the growth inhibitory activity of Mycobacterium tuberculosis H₃₇Rv. To validate the models, we synthesized twelve quinolines through the Friëdlander reaction and three indolinones. The synthesized compounds were evaluated in the growth inhibition of resistant H₃₇Rv tuberculosis strains (rpoB^S450L, katG^del, and gyrA^D94K) and in nontuberculous strains (M. avium and M. abscessus). We found that the compound (Z)-4-((2-oxoindolin-3-ylidene)amino)-N-(thiazol-2-yl)benzenesulfonamide was active in all resistant strains; the compound 2-(1H-indol-3-yl)-4-methylquinoline was active on M. avium; and the compound 10-methyl-11H-indeno[1,2-b]quinoline was active on M. abscessus. These models are useful for the discovery of new compounds with inhibitory properties of M. tuberculosis H₃₇Rv, and with potential applications in resistant and nontuberculous strains.