Organometallic Gold(III) Complex [Au(Hdamp)(L1⁴)]⁺ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease

Abstract

Chagas 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 against Trypanosoma cruzi, we evaluated both the in vitro and in vivo activity of the organometallic gold­(III) complex [Au­(III)­(Hdamp)­(L14)]Cl (L1 = SNS-donating thiosemicarbazone), henceforth denoted 4-Cl. Our results demonstrated that 4-Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In in vivo assays, 4-Cl in PBS solution loses the protonation and becomes the 4-neutral. 4-Neutral reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage at 2.8 mg/kg/day. All these changes resulted in the survival of 100% of the mice treated with the gold complex during the acute phase. Analyzing the surviving animals of the acute infection, the parasite load after 150 days of infection was equivalent to those treated with the standard dose of Bz without demonstrating the hepatotoxicity of the latter. In addition, we identified a modulation of interferon gamma (IFN-γ) levels that may be targeting the disease’s positive outcome. To the best of our knowledge, this is the first gold organometallic study that shows promise in an in vivo experimental model against Chagas disease.

Challenges in Chagas Disease Drug Development

“…Fexinidazole, an NTR-1-activated 5-nitroimidazole pro-drug [ 31 ], has been shown to outperform both benznidazole and nifurtimox as a curative treatment for experimental T. cruzi infections [ 34 ] ( Figure 2 A,B, as example), and a clinical trial to assess efficacy and tolerability against patients with asymptomatic chronic infections has been undertaken [ 35 ]. In addition, there have also been a number of recent studies reporting encouraging preliminary data on the antiparasite activities of other novel nitroaromatics [ 88 ], and of a new generation of diverse organometallic compounds [ 89 , 90 , 91 , 92 ].…”

Organometallic Gold(III) Complexes with Tridentate Halogen‐Substituted Thiosemicarbazones: Effects of Halogenation on Cytotoxicity and Anti‐Parasitic Activity

“…The increased lipophilicity after complexation enhances their cellular uptake, but also decreases their solubility in aqueous media, which is a serious drawback in terms of bioavailability, and can in worst case distort the obtained in vitro results. We came across such an effect when we re‐evaluated some of the previously determined in vitro parameters of the non‐halogenated complex 4‐H . Actually, we found that the previously determined CC 50 value for this compound was too high, most probably due to an insufficient solubility at higher concentrations.…”

“…Lopes and co‐workers showed the effective activity of the non ‐ halogenated [Au(dampH)(L‐H)]Cl . It eliminates both the extracellular trypomastigote and the intracellular amastigote forms of the parasite.…”

Nitroisatin dithiocarbazate: Synthesis, structural characterization, DFT, and docking studies

“…Intermolecular interactions of the best poses were analyzed by using the LigPlot software [23] with the conformational structures presented with PyMOL. The methodologies of the theoretical studies of molecular modeling performed here are similar in manner to previous works [24][25][26][27].…”