Coumarin-benzimidazole hybrids: Design, synthesis and identification of potential anticancer agents.

A series of coumarin-benzimidazole conjugates (6a-p) was designed and synthesized via a polyphosphoric acid (PPA)-mediated condensation of o-phenylenediamine derivatives with coumarin-3-carboxylic acids. The in vitro anticancer activity of all conjugates was evaluated against lung (A549) and breast (MCF7) cancer cell lines. Except for hybrids 6l (A549) and 6c (MCF7), all compounds exhibited notable cytotoxicity toward both cell lines, with IC50 values ranging from 0.85 ± 0.07 to 48.01 ± 0.45 μM. Among them, the unsubstituted derivative 6b emerged as the most potent compound, showing IC₅₀ values of 0.85 ± 0.07 μM (A549) and 1.90 ± 0.08 μM (MCF7). Compounds 6a, 6c, and 6g also demonstrated strong activity against A549 cells, with IC50 values of 1.86 ± 0.19 μM, 1.05 ± 0.09 μM, and 2.23 ± 0.13 μM, respectively. Furthermore, the potent conjugates 6b and 6g were found to be non-toxic toward Vero cells (LD50 > 100 μM), indicating selective cytotoxicity toward cancer cells. In silico molecular docking studies suggested that the activity of compound 6b against both cell lines may result from inhibition of sphingosine kinase 1 (SK1), whereas the potency of 6g against A549 cells could be attributed to cyclin-dependent kinase 2 (CDK2) inhibition. These computational predictions warrant further validation through target-specific biological assays. ADMET analysis further revealed that conjugate 6b possesses favorable pharmacokinetic properties, supporting its potential as a promising lead for future anticancer drug development.