Design and synthesis of novel pyridopyrimidine derivatives with anchoring non-coplanar aromatic extensions of EGFR inhibitory activity

The present study describes the synthesis of three series of 4-substituted pyridopyrimidin derivatives 4a-h, 5a-d. 6a-d, starting from 2-amino-6-(4-methoxyphenyl)-4-(4-(substituted) phenyl)nicotinonitrile 2a-d via the reaction with N,N-dimethyl-N-'substituted phenyl formimidamide to obtain 4a-h or with either phenyl isothiocyanate 1:1 and 1:2 to obtain 5a-d, 6a-d respectively. The synthesized compounds were evaluated for their effectiveness as EGFR inhibitors against Gefitinib. Six compounds; 4b,g,h, 5c and 6a,d prompted significantly higher EGFR inhibitory activity relative to that of Gefitinib. While two compounds 4d and 4f showed IC50 values non-significantly different from that of the reference drug. Furthermore, compounds 4a, 4 h, 6a and 6d were chosen to be assessed in vitro for their cytotoxicity against two EGFR-overexpressing cell lines; two human cancer cell lines namely: MCF7 and MDA-MB-361. Moreover, cell cycle analysis and apoptotic assay was applied for compound 4b that showed most potent inhibitory activity on EGFR, and the highest cytotoxicity against MCF7 and MDA-MB-361, where cell cycle arrest was achieved at pre G and S phases with increased apoptosis. Additionally, a molecular docking study was achieved to inspect the interaction of this compound with the active site of EGFR-TK.

Automated summary

The study synthesized pyridopyrimidin derivatives and evaluated their effectiveness as EGFR inhibitors. Six compounds showed higher inhibitory activity, while two compounds were similar to the reference drug. Further investigation was conducted on the cytotoxicity and mechanisms of action of four compounds, indicating the most potent inhibitory activity and high cytotoxicity.