Benzimidazole based bis-carboxamide derivatives as promising cytotoxic agents: Design, synthesis, in silico and tubulin polymerization inhibition

A new series of carboxamide-bearing benzimidazole derivatives have been reported for their cytotoxicity profile ( in vitro ) on selected human tumour cells like A549, HCT116, SK-Mel-28, and MCF-7. Among the derivatives, the utmost cytotoxicity was shown by compounds 10g and 10m , with specificity toward SK -Mel-28 skin cancer cells displaying potent IC50 values (0.41-51.21 mu M). The compounds 10g and 10m unveiled to be safe on testing them against human non-cancerous lung epithelial cells (BEAS: IC50: > 100 mu M). The annexin V binding assay and JC-1 were implemented to evaluate the scope of apoptosis and loss of mitochondrial transmembrane potential in SK-Mel-28 cell lines. The G2/M phase arrest in the cell cycle examination was observed by active molecule 10m dose-dependently. Target-based findings suggested tubulin polymerization inhibition by 10m (IC50 of 2.36 +/- 0.20 mu M) and its efficacious binding with DNA. The detailed binding interactions of compounds 10g and 10m with tubulin and DNA was examined by docking studies on PDB ID: 3E22 and DNA hexamer (PDB ID: 1NAB) respectively.(c) 2022 Elsevier B.V. All rights reserved.