Design, synthesis, and apoptotic antiproliferative efficacy of new quinazoline/1,3,4-oxadiazole-2-thione derived EGFR/HER-2 dual inhibitors with anti-breast cancer activity

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 GI₅₀ 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 IC₅₀ 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.