Design and synthesis of new quinazoline hybrid molecules as EGFR targeting anti-breast cancer agents and computational studies

Abstract

A new series of quinazoline-isoxazole derivatives (5a-o) were synthesized based on molecular hybridization approach and features of marketed EGFR inhibitors. The in vitro anti-breast cancer activity of compounds (5a-o) against MDA-MB-231 and MCF-7 cell lines revealed that five compounds (5e, 5 g, 5j, 5k and 5n) displayed good to remarkable activity against tested cancer cell lines (IC₅₀ = 2.95–12.12 μM). In specific, compounds 5k and 5n showed higher activity against MCF-7 cell line with IC₅₀ values of 3.18 and 2.95 μM respectively than the Doxorubicin (DOX) (IC₅₀ = 4.23 μM). Compound 5 g (IC₅₀ = 4.97 μM) showed comparable activity against MCF-7 cell line with the DOX. As well, compounds 5 g, 5k and 5n could act as potent in vitro EGFR inhibitors with IC₅₀ values of 0.421, 0.164 and 0.132 μM respectively as compared to Erlotinib (IC₅₀ = 0.073 μM). Molecular docking studies revealed the possible binding interactions of compounds 5 g, 5k, 5n and Erlotinib with EGFR (PDB ID 4HJO). Compounds 5 g, 5k and 5n displayed better binding energies and inhibition constants than the Erlotinib. The molecular dynamics simulations revealed that the RMSD plots of the protein 4HJO and compound 5n are significantly matching, with backbone RMSDs remaining stable through a 200 ns simulation period. Finally, compounds 5 g, 5k and 5n followed Lipinski and Veber rules in addition to their high GI and HIA absorptions.