Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity.

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds - showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound showed potent antiproliferative activity against these cell lines (IC = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53-79%) activity. Compound was found to be the most active compound against EGFR (IC = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound could be used as a potential anticancer agent.