New benzimidazole based hybrids: Synthesis, molecular modeling study and anticancer evaluation as TopoII inhibitors.

[Display omitted] • Series of new benzimidazole hybrids were synthesized. Antiproliferative activity was assessed against HepG-2, MCF-7, PC-3, HCT-116 and Hela cancer cells. • Compounds 13 , 20 , 21 , 22 and 23 were the most active anticancer agents. • Compound 21 showed the most potent anticancer activity with IC 50 range of 2.82 to 12.59 µM. • Compounds 13 and 20 were found to be the most potent TopoII inhibitors. • Compound 13 showed cell cycle arrest at S -phase, increasing in the total apoptosis by 62.5 folds and decreasing in TF-DNA binding in HepG-2 cells. Molecular docking studies and Lipinski's rule were conducted. Three series of new benzimidazole hybrids were designed and synthesized as promising human TopoII inhibitors. They were characterized by different spectroscopic techniques (1H, 13C NMR, ESI-MS and IR). All hybrids (6 – 23) were screened for their in vitro antiproliferative activity against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Compound 21 showed the most potent anticancer activity against all cancer cell lines, with IC 50 range of 2.82 to 12.59 µM, while proving safe towards normal cells WI-38 (IC 50 = 31.89 µM) compared to the reference drug doxorubicin (IC 50 = 6.72 µM). The most active candidates 13 , 20 , 21 , 22 and 23 were further assessed for their human TopoII inhibition. The best of which, compounds 13 and 20 showed IC 50 of 6.72 and 8.18 µM respectively compared to staurosporine (IC 50 = 4.64 µM). Further mechanistic studies for compound 13 showed cell cycle arrest at S -phase by 51.29 % and a significant increase in the total apoptosis by 62.5 folds. Furthermore, apoptosis study proved that it induced apoptosis by decreasing both IAP and Bcl-2, activating caspases 3, 8 and 9, and increasing accumulation of ROS in HepG-2 cells. Besides, it decreased transcription factors' binding activity to DNA. Comparative molecular docking study was performed between the most potent TopoII inhibitors 13 and 20 , and the least potent one 23 to relate the binding pattern with TopoII catalytic active site to the biological activity, where all results came in agreement with the biological results. Additional molecular modeling studies including surface mapping and contact preferences were performed to emphasize the importance of hydrophobicity. Physicochemical calculations were assessed where compounds 13 and 20 represented very promising orally active drug candidates. [ABSTRACT FROM AUTHOR]