Novel bis-benzimidazole-triazole hybrids: anticancer study, in silico approaches, and mechanistic investigation.

AIM: Benzimidazole-triazole conjugates are very active hotspot for design and synthesis of promising anticancer agents. The target analogs showed potent and selective cytotoxicity over different cancer cell lines for breast and lung ones. MATERIALS & METHODS: A new series of bis-1,4-disubstituted-1,2,3-triazoles moieties conjugated with a 2-mercapto-benzimidazole 4a-h and 7a-g was synthesized via the click cycloaddition (CuAAC) reaction. The synthesized triazoles were characterized using several spectroscopic tools. In addition, they were tested against variable cell lines representing different cancer types; HepG-2, MCF-7, HCT-116, and A-549. Computational experiments were introduced for understanding their structure-activity relationships. RESULTS & CONCLUSION: The data revealed the outperformance of 7a-g analogs over 4a-h one with very effective IC(50) values; 4-13 µg/mL compared to the reference drugs. Moreover, detailed mechanistic analyses showed potent Aurora-A Kinase expression for the most active analogs 7a and 7d exhibiting IC(50); 3.5 and 5.3 over the control cells 8 ng/mL respectively. Additionally, based on their Aurora-A Kinase inhibitory activity, compound 7a was promising in apoptosis induction and cell cycle arrest. Molecular docking studies with Aurora-A Kinase revealed binding behaviors similar to the co-crystallized ligand sunitinib. Finally, this scaffold exhibits cytotoxic activity via apoptosis, enzyme downregulation, and suppression of cell division.