Summary: | 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 <b>1</b>–<b>4</b> showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound <b>4g</b> showed potent antiproliferative activity against these cell lines (IC<sub>50</sub> = 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 <b>4g</b> showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79%) activity. Compound <b>4g</b> was found to be the most active compound against EGFR (IC<sub>50</sub> = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound <b>4g</b> revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound <b>4g</b> could be used as a potential anticancer agent.
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