Synthesis of new quinazoline-linked fused imidazole-oxazole conjugates; evaluation of anticancer activity, molecular docking, DFT and ADMET studies

Abstract

A novel series of quinazoline-linked fused imidazole-oxazole conjugates (9a-n) were synthesized and evaluated for their anticancer activity against two breast cancer cell lines such as MDA-MB231 and MCF-7 using the MTT assay. The erlotinib used as a standard reference drug. The anticancer activity outcomes shown that compound 9 l with IC₅₀ values of 18.20 ± 1.20 μM (MCF-7) and 21.13 ± 1.13 μM (MDA-MB231). Also, compounds 9i, 9j, and 9 k, displayed slightly lower activity, with IC₅₀ values ranging from 23.10 ± 1.32 μM to 34.02 ± 0.06 μM. Additionally, inhibition assays targeting the tyrosine kinase EGFR showed that compounds 9i, 9j, and 9 l exhibited the greatest EGFR tyrosine kinase inhibitory potency, with IC₅₀ values of 2.80 μM, 2.93 μM, and 2.20 μM, respectively. Biologically potent compounds showed stronger binding than erlotinib, with docking scores of −8.73 to −8.99 kcal/mol compared to −8.11 kcal/mol. Compound 9i, forming dual hinge hydrogen bonds, was more active than erlotinib, while 9 l achieved the best docking score due to strong hydrophobic interactions. DFT results confirmed higher dipole moments and favourable electronic features, supporting their anticancer potential. SWISS, ADME, and pkCSM were used to evaluate the pharmacokinetics of the potent compounds 9i, 9j, 9 k and 9 l. The four compounds (9i, 9j, 9 k and 9 l) closely fitted all four requirements, except Ghose rule.