Quinazoline fused 1,2,4-triazoles: PIDA-mediated synthesis, characterization, anti-breast cancer agents, ABTS radical scavenging efficacy, molecular docking, and DFT studies

Abstract

The present work demonstrates the PIDA-mediated mild synthesis of 3-aryl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazolines 5a-n through an intramolecular oxidative-cyclization of twelve electronically dissimilar and newly prepared (E)-4-(2- benzylidenehydrazineyl)-2-phenyl- quinazolines 4a-n as key precursors. Structural confirmation of quinazoline-hydrazone and triazole has been established based on 1H and 13C NMR, IR, and HRMS data. Antiproliferative activity examination has led to the identification of 5-phenyl-3-(2,3,4-trimethoxyphenyl)-[1,2,4] triazolo[4,3-c]quinazoline 5g and 3-(2,3- dichlorophenyl)-5-phenyl-[1,2,4]triazolo[4,3-c] quinazoline 5j, as most active (less than and comparable to standard), which exhibit cytotoxicity with IC50 value of 1.14 mM and 1.39 mM, respectively against MCF-7 cell line. 5g and 5j also show significant potential against MDA-MB231 cell line with IC50 of 2.79 mM and 1.95 mM, respectively. Additionally, molecular modeling studies have been conducted to support the results and to study the binding interaction of the compound 5g and 5j with VEGFR-2 kinase enzyme (PDB ID:3U6J). Furthermore, systematic screening of 5a-n for ABTS radical scavenging activity, displays that 3-(4-fluorophenyl)-5-phenyl-[1,2,4]triazolo[4,3-c]quinazoline 5h, has the highest antioxidant efficacy with IC50= 11.2 ± 0.14 μg/mL. The antioxidant efficacy of 5a-n is also supported by DFT studies.