Antileishmanial activity and insights into the mechanisms of action of symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes

Leishmania amazonensis and L. braziliensis are the main etiological agents of the American Tegumentary Leish-maniasis (ATL). Taking into account the limited effectiveness and high toxicity of the current drug arsenal to treat ATL, novel options are urgently needed. Inspired by the fact that gold-based compounds are promising candidates for antileishmanial drugs, we studied the biological action of a systematic series of six (1)-(6) sym-metric Au(I) benzyl and aryl-N-heterocyclic carbenes. All compounds were active at low micromolar concen-trations with 50% effective concentrations ranging from 1.57 to 8.30 mu M against Leishmania promastigotes. The mesityl derivative (3) proved to be the best candidate from this series, with a selectivity index ~13 against both species. The results suggest an effect of the steric and electronic parameters of the N-substituent in the activity. Intracellular infections were drastically reduced after 24h of (2)-(5) incubation in terms of infection rate and amastigote burden. Further investigations showed that our compounds induced significant parasites' morpho-logical alterations and membrane permeability. Also, (3) and (6) were able to reduce the residual activity of three Leishmania recombinant cysteine proteases, known as possible targets for Au(I) complexes. Our promising results open the possibility of exploring gold complexes as leishmanicidal molecules to be further screened in in vivo models of infection.

Automated summary

This study investigates the biological action of a series of gold-containing compounds on American Tegumentary Leishmaniasis. These compounds show inhibitory effects on Leishmania promastigotes in vitro and reduce intracellular infection. One compound is identified as the most promising candidate with high selectivity against both species.