Development of Au(I)-phosphine amino acid bioconjugates as potential antileishmanial agents

Leishmaniasis is one of the most important neglected tropical diseases worldwide, and current treatments are limited by toxicity, resistance, high costs, and prolonged regimens. This study investigated amino acid bioconjugation as a strategy to improve the selectivity and antileishmanial activity of Au(I)-phosphine complexes. Five complexes were synthesized and characterized. All compounds potently inhibited trypanothione reductase, exhibiting nanomolar IC₅₀ values. Leishmanicidal activity correlated with compound lipophilicity: Au(PPh₂PhCOO(Gly))Cl, Au(PPh₂PhCOO(Leu))Cl, and Au(PPh₂PhCOOCH₃)Cl showed EC₅₀ values of 12.9, 13.5, and 5.8 μM, respectively, whereas hydroxyl-containing derivatives displayed low or no activity. Most compounds were highly selective for trypanothione reductase over glutathione reductase (SI > 30), with Au(PPh₂PhCOO(Leu))Cl showing a selectivity index above 100. These findings demonstrate that amino acid bioconjugation effectively modulates the biological properties of Au(I)-phosphine complexes, highlighting their potential as antileishmanial agents.