Synthesis, biological evaluation and detailed computational studies of N-sulfonyl indole-based dihydrothiazoles against colorectal carcinoma.

A novel series of N-sulfonyl indole-based dihydrothiazole hybrids (5a-5u) was synthesized and comprehensively evaluated as potential anticancer agents against colorectal carcinoma. All compounds were structurally confirmed by NMR and HRMS and screened for cytotoxicity against HCT-116 colorectal cancer cells, with selectivity evaluated using CCD-1076Sk normal fibroblasts. Several derivatives displayed significantly higher potency than sorafenib, with compound 5d emerging as the lead molecule (IC50 = 4.10 µM, SI = 12.0).To elucidate the molecular basis of activity, induced-fit docking and MM-GBSA calculations were performed against four key colorectal cancer-related targets (TNF-α, PI3K p110α, AKT1, and mTOR). Compound 5d exhibited the most favorable multi-target binding profile, supported by highly stable ligand-protein interactions. Molecular dynamics simulations confirmed the dynamic stability of 5d, particularly with TNF-α and mTOR. In addition, DFT, ESP, and GCR analyses revealed that 5d combines optimal electronic reactivity with stability, while ADME predictions indicated a favorable pharmacokinetic profile. Overall, 5d is identified as a promising multi-target lead for colorectal cancer therapy.