Quinazoline Fused 1,2,4-triazoles: PIDA-Mediated Synthesis, Characterization, Anti-Breast Cancer Agents, ABTS Radical Scavenging Efficacy, Molecular Docking, and DFT Studies

Quinazoline Fused 1,2,4-triazoles as Anti-Breast Cancer and Antioxidant Agents

Abstract

The present work demonstrates the PIDA-mediated mild synthesis of 3-aryl-5-phenyl-[1,2,4] triazolo[4,3-c]quinazolines 5a-5n through an intramolecular oxidative-cyclization of twelve electronically dissimilar and newly prepared (E)-4-(2-benzylidenehydrazineyl)-2-phenyl- quinazolines 4a-4n as key precursors. Structural confirmation of quinazoline-hydrazone and triazole has been established based on ¹H & ¹³C-NMR, IR, and HRMS data. Antiproliferative activity examination 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 exhibits cytotoxicity with IC₅₀ value of 1.14 mM and 1.39 mM respectively against MCF-7 cell line. 5g and 5j also shows 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, systematically screening of 5a-5n for ABTS radical scavenging activity, displays that 3-(4-fluorophenyl)-5-phenyl-[1,2,4]triazolo [4,3-c] quinazoline 5h, has highest antioxidant efficacy, with IC₅₀ = 11.2 ± 0.14 µg/ml. The antioxidant efficacy of 5a-5n was also supported by DFT studies.