Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide...

Compounds with thiosemicarbazide and semicarbazide scaffolds are among the most promising structures in medicinal chemistry due to the possibility of forming multiple hydrogen bonds. Therefore, six new derivatives of 4-fluorophenoxyacetylthiosemicarbazide and 4-fluorophenoxyacetylthiosemicarbazide were designed to compare their physicochemical properties, biological activity, and in silico pharmacokinetic parameters. All compounds were characterized by ¹H, ¹³C NMR, ¹⁹F, IR spectra. For selected derivatives (AB2 and AB5), X-ray studies were performed to confirm their synthetic route and identify the tautomeric forms and intra- and intermolecular interactions occurring in the crystalline state. In the in silico pharmacokinetic study, a clear difference in lipophilicity was observed between thiosemicarbazide and semicarbazide derivatives. In vitro biological studies have shown the promising activity of thiosemicarbazides against prostate cancer cell line LNCaP, with a higher safety profile than semicarbazides. The most active compound AB2 showed IC₅₀ = 108.14 μM against LNCaP. Based on biological studies, topoisomerase IIα was proposed as a potential molecular target, which was confirmed by molecular docking studies.