Regioselective sulfenylation of indoles using sulfonyl hydrazides: In silico design, DFT calculation, hirshfeld surface analysis, ADMET study, molecular docking and anticancer activity

Abstract

We report the design, synthesis, and anticancer evaluation of some novel indole thioethers, constructed via an efficient and regioselective sulfenylation of indoles with sulfonyl hydrazides, facilitated by KSCN. This method offers a valuable tool for the synthesis of a variety of indole thioethers under mild reaction conditions with good to excellent yields. Initially, the drug like properties of all compounds were evaluated. Subsequently, six lead compounds were subjected to molecular docking studies targeting the active site of the B-RAF protein (PDB ID: 1UWH). These compounds demonstrated strong interactions with key amino acid residues, including Lys482 (3.47 Å), Gln529 (3.28 Å), Thr528 (2.85 Å), Phe467 (2.85 Å), Gly95 (2.86 Å), Thr598 (3.30 Å), His538 (3.37 Å), Ser535 (3.22 Å), and Asn579 (3.43 Å), suggesting their potential as anticancer agents. DFT calculations of the novel thioethers revealed their energy gaps and binding affinities, while Hirshfeld surface analysis highlighted significant intermolecular interactions within their crystal structures. In vitro cell-based assays were conducted on selected compounds to assess their cytotoxicity against human cancer cell lines. The results suggest that extending the exposure duration beyond 24 h may uncover significant cytotoxic effects. In conclusion, these compounds exhibit promising potential as anticancer agents against the tested human cancer cell lines. © 2025 Elsevier B.V.