Benzimidazole based hybrids as privileged candidates for topoII inhibition: Design, synthesis and molecular modeling studies

Two series of new benzimidazole derivatives were designed and synthesized. The antiproliferative activity of the new derivatives was screened against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Relative to Doxorubicin (IC50 = 6.72 mu M), compounds 18 and 19 showed broad spectrum anticancer effect against all the tested cancer cell lines, with IC50 range of 5.16-20.35 mu M, however they were safe to WI-38 normal cells with IC50 of 32.61 mu M and 50.62 mu M, respectively. Inspection of human TopoII inhibitory activity disclosed that compound 18 was the most potent (IC50 = 6.9 mu M) compared to Staurosporine (IC50 = 4.64 mu M). Further mechanistic studies implied that compound 18 triggered the apoptotic death of MCF-7 cells via decreasing Bcl-2, activating caspases 8 and 9, and increasing the accumulation of ROS. In addition, it caused cell cycle arrest at the G1-phase and lowered the binding activity of transcription factors' protein to DNA. The biological results were assisted by molecular modeling studies. The physicochemical parameters of compounds 18 and 19 conferred convenient drug-like properties.