Iron-Catalyzed Synthesis of Ferrocenyl–Thioether Conjugates via C–S Cross-Coupling of Thioethers and Vinylic Chlorides: Construction, Anticancer, and Computational Studies

Herein, a library of ferrocenyl–thioether derivatives of acrylaldehyde and acrylonitrile is developed via a direct C–S bond formation reaction under mild conditions. Various aromatic and aliphatic thiols were successfully coupled with ferrocenyl acrylaldehyde/acrylonitrile in the presence of a chalcogen-stabilized iron–carbonyl cluster (Fe₃Se₂(CO)₉). All the reactions were carried out in water under aerobic conditions, and the transformation of a wide range of ferrocenyl–thioether derivatives in good yields were obtained. Furthermore, cytotoxicity studies of some selected ferrocenyl–thioethers were performed against the prostate cancer cell line (PC-3) and normal human embryonic kidney cell line (HEK). 3-Ferrocenyl-3-(4-trifluoromethyl)-phenylsulfanyl was found to be significantly active. It showed an IC₅₀ of 5.5 μM toward prostate cancer cell lines. Moreover, it also showed activity comparable to that of standard anticancer drugs including axitinib, nelfinavir, thymitaq, and (±) thioridazine. The anticancer activity was further supported by density functional theory calculations including the HOMO–LUMO energy gap, cyclic voltammetry, UV–vis studies, molecular docking, and reactive oxygen species analysis. All compounds synthesized in this report are new, and they may serve as milestones in the futuristic research of anticancer drugs.