Gold(I) N-heterocyclic carbenes have been explored for their therapeutic potential against several diseases. Neglected tropical diseases, including leishmaniasis, Chagas disease, and viral infections, such as zika, mayaro, and chikungunya, urgently require new treatment options. The emergent SARS-CoV-2 also demands significant attention. Gold complexes have shown promise as alternative treatments for these conditions. Previously, gold(I)(1,3-bis(mesityl)imidazole-2-ylidene)Cl (AuIMesCl) demonstrated significant leishmanicidal and anti-Chikungunya virus activities. In this study, we synthesized and fully characterized a series of gold(I)(1,3-bis(mesityl)imidazole-2-ylidene)(SR) complexes, where SR includes thiolate donor species such as 1,3-thiazolidine-2-thione, 1,3-benzothiazole-2-thione, 2-mercaptopyrimidine, and 2-thiouracil. These compounds were stable in solution, and ligand exchange reactions with N-acetyl-L-cysteine indicated that complexes with SR ligands are more labile than those with chloride. Although the reactions are rapid, they reach equilibrium at varying molar ratios depending on the SR ligand. The increased lability of these compounds results in higher cytotoxicity to host cells, such as Vero E6 and bone marrow-differentiated macrophages, compared to AuIMesCl. Despite this, the compounds effectively inhibited viral replication, achieving 95.5% inhibition of Zika virus replication at 2 μM with 96% host cell viability. Although active at low concentrations (∼2 μM) against Leishmania (L.) amazonensis and Trypanosoma cruzi, their high cytotoxicity for macrophages confirmed AuIMesCl as a better candidate with a higher selectivity index. This work correlates the coordination chemistry of pyrimidines and thiazolidines with their in vitro biological activities against significant diseases.

The quest for new drug candidates targeting neglected parasitic diseases has become increasingly urgent over the past decades. Advancements in formulating and optimizing drug delivery systems begin with basic research, including direct assays to evaluate the activity of molecules against parasitic stages maintained in laboratories; i.e., promastigotes. In the context of leishmaniasis, an endemic disease worldwide, the cultivation of Leishmania parasites can vary significantly across different laboratories. Factors such as culture media composition, pH, supplementation, and temperature can lead to varied drug responses in in vitro activity assays. This study aims to compile the parameters used in Leishmania spp. promastigotes cultivation protocols described in scientific articles published in indexed journals over the past ten years. The data reveal a lack of uniformity among Leishmania culture protocols, suggesting a potential bottleneck in comparing the leishmanicidal potential of in vitro drug candidates reported by different research groups. This condition is crucial to consider, because viability/inhibition assays should begin with fully-grown, healthy promastigote cultures capable of homogeneous division, thereby producing more reproducible results.

(1) Background: Leishmaniasis refers to a group of anthropozoonotic diseases caused by Leishmania. The major chemotherapeutic agent used for its treatment is Glucantime^®®, but the search continues for new compounds that are economically viable and act on the protozoan without causing damage to the host cell. As an alternative approach, this study used a combination of copaiba oil (CO) and kojic acid (KA) to determine their in vitro action on host cells, on the Leishmania (Leishmania) amazonensis protozoan and its interaction with macrophages. (2) Methods: In vitro culture, analysis of cytokine release and microscopy assays were performed. Statistical analysis was performed with ANOVA (GraphPad Prism). (3) Results: The combination did not induce cytotoxic effects on macrophages after treatment but promoted morphological changes in the protozoan, such as nuclear alterations (apoptotic characteristics), alterations in the cellular body and an increase in the number of electrodense structures and acidocalcisomes, observed mainly at the concentrations of CO20KA50 and CO30KA50 μg/mL. We observed reductions in the intracellular amastigote number and in the production of proinflammatory cytokines, such as IL-6 and TNF-α, after treatment with CO30KA at 50 µg/mL. (4) Conclusions: We report here, for the first time, that the combination of CO and KA may be a promising approach against Leishmania (Leishmania) amazonensis.

Metal-based compounds are emerging as promising alternatives for the treatment of neglected parasitic and viral infections, which urgently require new therapeutic strategies due to limited effective drugs. In this study, a series of [Pt(II)(phpy)(PR₃)Cl] complexes, where phpy is 2-phenylpyridine and PR₃ represents triphenylphosphine (PPh₃), 1,3,5-triaza-7-phosphaadamantane (PTA), para-benzoic acid-diphenylphosphine (PPh₂PhCOOH), or tris(2-carboxyethyl)phosphine (TCEP), were synthesized and systematically evaluated for their chemical properties and in vitro biological activities. Chemical reactivity, including ligand exchange with Histidine and N-acetylcysteine, hydrophilic/lipophilic balance, and interactions with bovine serum albumin and DNA, was correlated with biological outcomes. The novel TCEP complex exhibited exceptional chloride stability and intrinsic fluorescence but lacked antiviral and antileishmanial activity. The PTA derivative showed selective antileishmanial activity, achieving a selectivity index (SI) of 10.8 and reducing the infectivity index by 40% at 12 µM. Also, PTA showed selective antitumor activity in ovarian cancer (SI 9.1). In contrast, the PPh₂PhCOOH derivative demonstrated significant antiviral activity, inhibiting Mayaro virus and Zika virus replication by 94% and 78%, respectively, at 50 µM. These findings underscore the potential of coordination chemistry to fine-tune biological activity and support the rational design of metal-based therapeutics for neglected diseases.

Leishmaniasis poses a significant public health challenge, highlighting the urgent need for safer and more effective therapies. Here, we investigated the antileishmanial activity and mechanism of action of gold(I)-triphenylphosphine complexes against Leishmania amazonensis . AuPPh ₃ Cl and AuPPh ₃ MTZ showed potent activity against promastigote and axenic amastigotes, with low micromolar EC ₅₀ and favorable selectivity toward mammalian cells. Both compounds reduced infection rate and parasite burden in infected macrophages. Mechanistically, the complexes targeted mitochondrial function, resulting in increased oxygen consumption associated with dissipation of the mitochondrial membrane potential, without affecting respiratory coupling. These findings were accompanied by increased mitochondrial superoxide production, indicating a pro-oxidant effect. AuPPh ₃ Cl induced higher hydrogen peroxide levels than AuPPh ₃ MTZ , suggesting ligand-dependent differences in redox modulation. In addition, treated parasites displayed elevated NADPH levels, consistent with the activation of compensatory antioxidant responses. Both compounds inhibited trypanothione reductase activity in parasite extracts and with the purified enzyme. Notably, AuPPh ₃ Cl showed greater selectivity toward the parasite enzyme over human glutathione reductase. Overall, these findings support a multitarget mechanism involving mitochondrial dysfunction and disruption of the trypanothione-dependent redox system, leading to oxidative imbalance and parasite death. Gold(I)-triphenylphosphine complexes represent promising candidates for the development of novel antileishmanial agents.