Silver(i) complexes bearing heterocyclic thioamide ligands with NH2 and CF3 substituents: effect of ligand group substitution on antibacterial and anticancer properties

Abstract

In recent years, there has been an increasing interest in the study of Ag(I) coordination compounds as potent antibacterial and anticancer agents. Herein, a series of Ag(I) complexes bearing phosphines and heterocyclic thioamide ligands with highly electronegative NH₂- and CF₃-group substituents, i.e. [AgCl(atdztH)(xantphos)] (1), [Ag(μ-atdztH)(DPEphos)]₂(NO₃)₂ (2), [Ag(atdzt)(PPh₃)₃] (3), [Ag(μ-atdzt)(DPEphos)]₂ (4), and [Ag(μ-mtft)(DPEphos)]₂ (5), where atdztH = 5-amino-1,3,4-thiadiazole-2-thiol, mtftH = 4-methyl-5-(trifluoromethyl)-1,2,4-triazol-3-thiol, xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and DPEphos = bis(2-diphenylphosphino-phenyl)ether, were synthesized, and their in vitro antibacterial and anticancer properties were evaluated. Complexes 1–4 bearing the NH₂-substituted thioamide exhibited moderate-to-high activity against S. aureus, B. subtilis, B. cereus and E. coli bacterial strains. A high antiproliferative activity was also observed for 1–3 against SKOV-3, Hup-T3, DMS114 and PC3 cancer cell lines (IC₅₀ = 4.0–11.7 μM), as well as some degree of selectivity against MRC-5 normal cells. Interestingly, 5 bearing the CF₃-substituted thioamide is completely inactive in all bioactivity studies. Binding of 1–3 to drug-carrier proteins BSA and HSA is reasonably strong for their uptake and subsequent release to possible target sites. The three complexes show a significant in vitro antioxidant ability for scavenging free radicals, suggesting likely implication of this property in the mechanism of their bioactivity, but a low potential to destroy the double-strand structure of CT-DNA by intercalation. Complementary insights into possible bioactivity mechanisms were provided by molecular docking calculations, exploring the ability of complexes to bind to bacterial DNA gyrase, and to the overexpressed in the aforementioned cancer cells Fibroblast Growth Factor Receptor 1, affecting their functionalities.