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

A. LUCZYWO; M. SOTO; G. C. MUSCIA; G. ROMANELLI; G. SATHICQ; C. GONZALEZ; J MELLA; M. MELLADO; S. ASÍS

ChemistrySelect

Wiley

Año: 2023

2365-6549

Tuberculosiswas discoveredmorethan a centuryago, and it isstill a diseasethat presentsdifficultiesin its treatmentdue tothe appearanceof newresistantstrains.To designnewantituberculosisagentswitha quinolinestructure,our groupdevelopedthree-dimensionalstructure-activityrelationship(3D-QSAR)models,basedon ComparativeMolecularFieldAnalysis(CoMFA)and ComparativeMolecularSimilarityIndexAnalysis(CoMSIA).Statisticallyrobustmodels(q2>0.6; r2ncv>0.8; r2pred>0.7) and withgoodexternalpredictabilitywereobtained.We foundthat positions2, 3, and 4 of the quinolinenucleusare directlyrelatedto the modulationof the growthinhibitoryactivityofMycobacteriumtuberculosisH37Rv. Tovalidatethe models,we synthesizedtwelvequinolinesthroughthe Friëdlanderreactionand threeindolinones.The synthesizedcompoundswereevaluatedin the growthinhibitionofresistantH37Rv tuberculosisstrains(rpoBS450L, katGdel, andgyrAD94K) and in nontuberculousstrains(M.aviumandM.ab-scessus).We foundthat the compound(Z)-4-((2-oxoindolin-3-ylidene)amino)-N-(thiazol-2-yl)benzenesulfonamidewas activein all resistantstrains;the compound2-(1H-indol-3-yl)-4-meth-ylquinolinewas activeonM.avium;and the compound10-methyl-11H-indeno[1,2-b]quinolinewas activeonM.abscessus.Thesemodelsare usefulfor the discoveryof new compoundswithinhibitorypropertiesofM.tuberculosisH37Rv, and withpotentialapplicationsin resistantand nontuberculousstrains