Synthesis and In Silico Studies of New Tetrahydrobenzo[b]Thiophenes and Heteroannulated Candidates as Antiproliferative Agents

Cancer remains a major global health challenge, emphasizing the need for new therapeutic agents. A series of tetrahydrobenzo[b]thiophene derivatives was synthesized from a β-enaminonitrile precursor and designed to target tubulin, a key protein in mitosis. The purity of compounds obtained was checked and confirmed with HPLC analysis. Antiproliferative activity was assessed against MCF-7 (breast) and HepG2 (liver) cancer cell lines, and cytotoxicity against the non-cancerous WI-38 cell line identified N-phenylamino- and N-benzyl-tetrahydrobenzo[b]thienopyrimidines as the most potent, likely due to their hydrophobic nature. The selectivity index showed the more selective toxicity of these derivatives toward cancer cells rather than normal cells. Molecular docking revealed strong binding affinities and favorable interactions to tubulin protein (PDB ID: 5NM5), predicted to resemble the co-crystallized ligands GTP and Colchicine (LOC). Pharmacokinetic modeling confirmed compliance with Lipinski’s, Veber’s, and Ghose’s rules, supporting favorable drug-likeness and bioavailability. These results point to the synthesized compounds as promising candidates for the development of novel anticancer agents.