Synthesis, biological evaluation and QSAR studies of a novel series of annelated triazolo[4,3-c]quinazolines

A series of novel annelated triazolo[4,3-c]quinazolines 6a-m have been synthesized and characterized by physicochemical as well as spectral means. The bioactivity assay for the newly synthesized compounds against Gram-positive and Gram-negative bacteria, and fungi indicates that most new compounds exhibit good antibacterial and antifungal activities in comparison with standard drugs. 2-[(4-Methoxyanilino)methy1]-5-phenyl-2,3-dihydro[1,2,4] triazolo[4,3-c]quinazoline-3-thione 6f, and 2-[(4-aminoanilino)methy1]-5-pheny1-2,3-dihydro[1,2,4]triazolo [4,3-c] quinazoline-3-thione 6m have emerged as the most potent antimicrobial agents with activity (pMIC(am), = 2.26 and 2.38 mu M/mL respectively) almost equal to the reference drugs streptomycin, penicillin and amphotericin B. The results of QSAR studies demonstrate that antibacterial, antifungal and over all antimicrobial activities of synthesized quinazoline derivatives are governed by electronic parameter, hydrophobicity (log P) and chemical potential (mu). The validity of Hammett's linear free energy relationship for the first time has been verified, from the linear plot of log activity against substituent constant (sigma). The observed low residual activity and high cross validated q(2) values indicate the predictive ability of the developed models, which further simplify the design and synthesis of new biologically potent molecules.