Abstract
A series of new multi-target inhibitors derived from quinazoline and 1,3,4-oxadiazole-2-thione were designed, synthesized, and tested in vitro for their antiproliferative efficacy. Compounds 7a, 7e, 7h, 7k, and 7l exhibited the most significant antiproliferative activity, with GI(50) values of 30, 26, 39, 35, and 32 nM, respectively. The in vitro inhibitory effects of compounds 7a, 7e, 7h, 7k, and 7l against the EGFR, BRAF(V600E), and HER-2 isozymes were examined. Compounds 7h and 7k were identified as the most potent multi-target inhibitors, with IC(50) values of 76 ± 4 (EGFR), 33 ± 2 (HER-2), and 48 ± 3 (BRAF(V600E)) for 7h, and 71 ± 4 (EGFR), 29 ± 1 (HER-2), and 45 ± 3 (BRAF(V600E)) for 7k, respectively. Compounds 7h and 7k markedly elevated the levels of caspase-3, caspase-8, and Bax proteins in the MCF-7 cancer cell line, while simultaneously reducing the levels of the anti-apoptotic protein Bcl-2. Computational studies provided insights into the binding interactions and stability of 7k with EGFR and HER-2. Density functional theory (DFT) and molecular electrostatic potential (MEP) analyses further confirmed the electronic stability and reactivity of FT-7k, highlighting its optimized structural and electronic properties for receptor binding. ADME predictions indicated that 7k possesses favorable pharmacokinetic properties, making it a promising candidate for further development.