Ligand Basicity Governs Cysteine Reactivity in Au(I)–NHC Thiolate Complexes: A Computational Study

Gold-thiolate compounds have emerged as promising therapeutic agents, showing activity against parasites such as <i>Leishmania amazonensis</i> and <i>Trypanosoma cruzi</i>, as well as viruses including Mayaro, Zika, and SARS-CoV. However, their use is limited by speciation due to the rapid ligand exchange with thiolated biomolecules, and control of this reactivity is key for the design of drugs. This study explores the reactivity of linear Au(I) complexes featuring the NHC, 1,3-bis(mesityl)imidazole-2-ylidene (IMes), and thiol-donating ligands, specifically pyrimidine-2-thione (HSpym), 2-thiouracil (2tuH), 1,3-thiazolidine-2-thione (HStzn), and 1,3-benzothiazole-2-thione (HSbtz), along with a chloride complex, Au(IMes)Cl, focusing on their interaction with the biologically significant amino acid cysteine. Thiol-donor ligands were selected for their structural diversity, biological relevance, and presence in drug-like molecules, allowing a systematic comparison of their reactivity with cysteine. Using DFT, we calculated Gibbs free energy variations that corresponded well with experimental equilibrium data from the ¹H NMR measurements. Electronic structural parameters and ligand basicity provided insights into the observed thermodynamic trends, with complexes containing the most basic ligands, Stzn and 2tu, reacting more extensively with cysteine. Among three proposed reaction mechanisms, we identified a preferred pathway, suggesting that the leaving ligand may participate in cysteine deprotonation. In this mechanism, the initial exchange with protonated cysteine was most favorable for Au(IMes)Spym, while deprotonation of the intermediate proceeded most rapidly with Au(IMes)Cl. These findings elucidate the influence of ligand characteristics on heteroleptic Au(I)(NHC) complex reactivity, contributing to the understanding of these complexes as prospective therapeutic agents.