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.