Design, Synthesis, and Evaluation of Benzimidazole-Carbazole Hybrids Targeting Heat Shock Proteins-Mediated Apoptosis...

Heat shock proteins (HSPs), particularly HSP70 and HSP90, are pivotal molecular chaperones implicated in cancer progression and resistance mechanisms. Dual inhibition of these chaperones represents a promising therapeutic approach. Here, we report the design and synthesis of a novel series of benzimidazole-carbazole hybrids aimed at targeting HSP70/90. Leveraging the kinase inhibitory properties of benzimidazole and the DNA interfering and apoptotic potential of carbazole, these hybrids were evaluated for their anticancer activity against breast (MCF-7) and colon (HCT-116) cancer cell lines. The most active compounds demonstrated submicromolar IC₅₀ values and induced apoptosis through mitochondrial dysfunction and cytoskeletal disruption, confirmed via flow cytometry and fluorescence microscopy. Molecular docking revealed high binding affinities to HSP70 (PDB: 1S3X) and HSP90 (PDB: 1YC4), correlating with experimental outcomes. Furthermore, DNA interaction studies confirmed the compounds' ability to induce structural destabilization and fragmentation, providing insight into their mechanism of action. These findings highlight the potential of benzimidazole-carbazole hybrids as promising HSP inhibitors for overcoming cancer resistance.