New phthalimide-based derivatives as EGFR-TK inhibitors: Synthesis, biological evaluation, and molecular modeling study

A novel series of phthalimide derivatives was synthesized and evaluated for in vitro antitumor activity against six human cancer cell lines; HepG-2, HCT-116, MCF-7, Hep2, PC3 and Hela.The obtained results revealed that compound 32 was the most potent antitumor, while compounds 33, 22 and 24 showed strong activity against all tested cell lines. Further biological evaluation of the most active compounds was done and their in vitro EGFR-TK inhibition was tested, and the results came in accordance with the results of antitumor testing, where 32 displayed promising inhibitory activity (IC50 = 0.065 mu M) compared to the standard drug erlotinib (IC50 = 0.067 mu M). In addition, compounds 48, 22, 28 and 19 showed strong inhibitory activity (IC50 = 0.089, 0.093, 0.147 and 0.152 mu M respectively). Cell cycle analysis was conducted and the results revealed that 32 induced cell cycle arrest on Hela and MCF-7 at G0-G1 phase and Pre-G1 phase causing cell death mainly via apoptosis. Additionally, in vivo antitumor screening revealed that 32 reduced both body weight and tumor volume in solid tumor utilizing Ehrlich ascites carcinoma (EAC) animal model. Molecular modeling study showed that 32 and 48 have the highest affinity for binding with the active site of EGFR-TK with docking score comparable to erlotinib. Compounds 32 and 48 could be used as template models for further optimization.

Automated summary

A series of novel phthalimide derivatives were synthesized and evaluated for their in vitro antitumor activity. Compound 32 showed the most potent activity, while compounds 33, 22, and 24 exhibited strong activity against all tested cell lines. Compound 32 also displayed promising EGFR-TK inhibition activity, making it a potential template for further optimization.