Design, synthesis, and computational study of hybrid quinazoline 1,3,5-triazines as epidermal growth factor receptor (EGFR) inhibitors with anticancer activity.

We report a series of hybrid quinazoline-1,3,5-triazine derivatives as EGFR inhibitors, which were synthesized and tested using a variety of in vitro, in silico, and in vivo studies. The derivatives were found to be active against different cancer and non-toxic against normal cell lines, with compounds 7c , 7d , 7e , and 7j being the most potent ones. The derivatives were also evaluated for angiogenesis inhibition potency in chicken eggs and molecular docking and dynamics simulation studies were carried out to elucidate fundamental substituent groups essential for their bioactivity. Additionally, a SAR study of the derivatives was performed for future compound optimization. These studies suggested that the derivatives have a high affinity towards EGFR with favourable pharmacological properties. The most active compound ( 7e ) was further evaluated for in vivo anticancer activity against DMBA induced tumour in female Sprague-Dawley rats as well as its effects on plasma antioxidant status, biotransformation enzymes, and lipid profile. The study suggested that the 7e compound has lead properties against breast cancer and can serve as a starting compound for further development of anti-EGFR compounds.