Ayelen LuczywoMauricio SotoGisela C. MusciaGustavo P. RomanelliGabriel SathicqCésar GonzálezMella, JaimeJaimeMellaMarco MelladoSilvia E. Asís2025-04-132025-04-132023-05-2210.1002/slct.2023000422-s2.0-85160423614https://cris-uv-2.scimago.es/handle/123456789/1941WOS:000992215900001Abstract 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 2 ncv >0.8; r 2 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 H 37 Rv. 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 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‐(1 H ‐indol‐3‐yl)‐4‐methylquinoline was active on M. avium ; and the compound 10‐methyl‐11 H ‐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.enacceso restringidoChemistry, MultidisciplinaryChemistryarticle