Organometallic gold(III) [Au(Hdamp)(L14)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection

Abstract

AbstractChagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs againstTrypanosoma cruzi, we evaluated both thein vitroandin vivoactivity of the organometallic gold(III) complex [Au(Hdamp)(L14)]Cl (L1 =SNS- donating thiosemicarbazone), which was denoted 4-Cl. Our results demonstrated that 4- Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and the intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In very-low-dosein vivoassays, 4-Cl reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage. All these changes resulted in the survival of 100% of the mice treated with 4-Cl during the acute phase. We hypothesised that 4-Cl can act directly on the parasite and may participate in the modulation of IFN-γ production at the acute stage of the disease. Molecular docking simulations showed that the compound may interact with cruzain, a thiol protease considered a possible antiparasitic drug target, primarily by hydrophobic interactions. These analyses predicted that the Cys25 residue in the cruzain binding site is approximately 3.0 Å away from the S and Au atoms of the gold compound, which could suggest formation of a possible covalent bond between cruzain and the inhibitor. Overall, we confirmed the potential of 4-Cl as a new candidate for Chagas disease treatment.