Design and Synthesis of New Quinazoline Hybrid Molecules as EGFR Targeting Antibreast Cancer Agents and Computational Studies

Abstract Some new quinazoline‐thiazolidine‐2,4‐dione‐1,2,3‐triazole hybrid molecules were synthesized ( 7a‐n ) using the Knoevenagel condensation and Cu‐catalyzed azide‐alkyne cycloaddition (CuAAC) as kssey approaches. The in vitro antibreast cancer activity of hybrid molecules ( 7a‐n ) revealed that compound 7j (IC 50 = 3.1–6.8 µM) displayed greater activity against MDA‐MB‐231 and MCF‐7 cancer cells than the standard drug Erlotinib (IC 50 = 4.7–7.4 µM). Compounds 7d and 7l have also shown higher activity against the MCF‐7 cell line than the positive control, with IC 50 values of 4.2 and 3.8 µM, respectively. As well, potent antibreast cancer compounds 7c ‐ d and 7j‐l have possible selectivity against tested breast cancer cells (SI values of 1.05–5.51). Further, in vitro anti‐EGFR activity was carried out for the potent antibreast cancer compounds and found that compound 7j (IC 50 ; 0.35 µM) showed higher activity than Erlotinib (IC 50 ; 0.44 µM). As well, compounds 7d and 7l demonstrated promising activity in comparison to Erlotinib with IC 50 values <1 µM. The in silico molecular docking studies revealed the important binding interactions of compounds 7c ‐ d and 7j‐l with the EGFR (PDB ID: 4HJO) and same compounds showed better binding energies and inhibition constants as compared to the Erlotinib. The in silico ADMET studies revealed that compounds 7c and 7d followed all the rules of Lipinski, Ghose, Veber, Egan, and Muegge without any deviation. Finally, most antibreast cancer anti‐EGFR compound 7j was characterized by density functional theory (DFT) with B3LYP/6‐311++G (d,p) basis set using Gaussian 09.