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

Luczywo, Ayelen; Soto, Mauricio; Muscia, Gisela C.; Romanelli, Gustavo P.; Sathicq, Gabriel; Gonzalez, Cesar; Mella, Jaime; Mellado, Marco; Asis, Silvia E.


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 (q(2)>0.6; r(ncv)(2)>0.8; r(pred)(2)>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 H(37)Rv. To validate the models, we synthesized twelve quinolines through the Friedlander reaction and three indolinones. The synthesized compounds were evaluated in the growth inhibition of resistant H(37)Rv 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 H(37)Rv, and with potential applications in resistant and nontuberculous strains.

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Título según WOS: ID WOS:000992215900001 Not found in local WOS DB
Título de la Revista: CHEMISTRYSELECT
Volumen: 8
Número: 20
Fecha de publicación: 2023


Notas: ISI