Targeting breast cancer with rationally designed quinazolines: A scaffold hopping strategy

•Novel anticancer agents designed using a scaffold hopping strategy.•Compound 5h showed higher cytotoxicity potential over erlotinib.•In silico and in vitro mechanistic studies shed light on 5h's activity.•Promising novel leads for targeted cancer therapy. A novel series of 4-anilinoquinazoline derivatives obtained from a scaffold hopping strategy was designed and synthesized as anticancer agents. Among the synthesized derivatives, compound 5h displayed the best anticancer activity against MCF7 and MDA-MB-231 breast cancer cells, with IC50 values of 0.35 μM and 0.45 μM, respectively. Notably, these values were more potent than those of the FDA approved erlotinib, which had IC50 values of 3.571 μM and 0.546 μM for MCF7 and MDA-MB-231, respectively. Mechanistic studies revealed 5h arrested cell cycle in the G2/M phase induced apoptosis more effectively than erlotinib. Further investigations into the mode of action of the synthesized derivatives included EGFR and HER2 kinase assays. Reverse virtual screening and in silico mechanistic studies were carried out to elucidate the activity of the synthesized derivatives. The findings underscore the potential of these novel derivatives, particularly compound 5h, as promising candidates for further development as anticancer agents. [Display omitted]