Isatin-Schiff s base and chalcone hybrids as chemically apoptotic inducers and EGFR inhibitors; design, synthesis, anti-proliferative activities and in silico evaluation

Isatin derivatives have been found to possess anti-proliferative effects against different human cancer cell lines. A series of isatin-Schiffs base and chalcone were synthesized and screened for their anticancer activities against three human cell lines which are: MCF-7, HepG-2, and HCT-116. All the tested compounds exhibited moderate to high antitumor activity with IC50 ranging from 0.68-35.60 mu M compared to Imatinib as a reference standard. Compounds 2b, 5, 8b, 12, 13a and 13b were the most active, with IC50 ranging from 0.68 to 5.85 mu M for the three cell lines. The most active structures were selected for further investigations. Firstly, the IC50 values on normal human cells (WI-38) have been studied to ensure the safety of our hits, which showed that our new compounds have exhibited (IC50 >165.98 mu M) as far as their cytotoxic effect is concerned. Moreover, up-regulation of BAX and Caspase-3 and down-regulation of Bcl-2 resulted in the induction of apoptosis from those active compounds. Further work has shown that the most potent derivative 8b, caused cell cycle arrest at the G2/M phase. Also, EGFR inhibitory activity for 8b showed IC50 0.014 mu M versus wild EGFR(WT) and 12.66 nM versus the mutant type, Lapatinib, and Erlotinib were used as reference standards with IC50 values of 0.025, 0.0653 jaM and 35.72, 59.56 nM versus both, respectively. Furthermore, the in-silico assessment showed that all-potent compounds were orally bioavailable without blood-brain barrier permeation. Finally, the molecular docking of 8b inside the active site of EGFR (1M17) showed a good binding through three hydrogen bonds and one arene-cation interaction. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

Isatin derivatives exhibit significant anti-tumor activity against three human cancer cell lines by inducing apoptosis and cell cycle arrest. The compounds also show effective EGFR inhibitory activity and oral bioavailability without blood-brain barrier permeation. Molecular docking studies revealed a strong binding of the most potent derivative inside the active site of EGFR.