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

## TL;DR

This study uses computational methods to understand how the basicity of ligands affects the reactivity of gold complexes with cysteine, which is important for designing better therapeutic agents.

## Contribution

The study identifies ligand basicity as a key factor governing cysteine reactivity in Au(I)–NHC thiolate complexes.

## Key findings

- Complexes with more basic ligands (Stzn and 2tu) react more with cysteine.
- Au(IMes)Cl shows faster deprotonation of intermediates compared to other complexes.
- The preferred reaction mechanism involves the leaving ligand in cysteine deprotonation.

## Abstract

Gold–thiolate compounds have emerged as promising
therapeutic
agents, showing activity against parasites such as Leishmania amazonensis and Trypanosoma
cruzi, 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.