Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC50 range 15.8–26.1 μg/mL) in comparison with benznidazole and nifurtimox (LC50 range 33.1–46.7 μg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90–60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents.

The pathogenesis of type 2 diabetes (T2D) is associated with a progressive loss of pancreatic β-cell mass. It is known that miR-146a, miR-34a, and miR-375 are involved in β-cell functionality. In this work, we evaluated the levels of these miRNAs in normal-glycaemic individuals, pre-diabetic, and T2D patients in relation to β-cell functionality, insulin resistance, and metabolic parameters. The relative expression of the miRNAs was evaluated in serum samples by real-time polymerase chain reaction. In a principal component analysis, we observed that T2D patients and pre-diabetic individuals were not associated with β-cell functionality. However, in a correlation matrix analysis, we detected that miR-34a was related to miR-146a and insulin resistance.The relative expression of miR-375 was correlated with cholesterol and low-density lipoprotein levels. A decrease of β-cell function in pre-diabetic individuals and T2D patients was observed. The insulin resistance was higher in pre-diabetic individuals and T2D patients. The relative expression of miR-146a in pre-diabetic individuals, T2D patients with insulin treatment, and T2D patients with nephropathy and diabetic foot was decreased. In addition, miR-34a was increased in T2D patients who were overweight and obese. The relative expression of miR-375 was increased in T2D patients with poor glycaemic control, while a decrease was seen in T2D patients with nephropathy and diabetic foot. Circulating miR-375, miR-34a, and miR-146a were not associated with β-cell functionality, but their expression was differentially affected by glycaemia, obesity, insulin treatment, and the presence of nephropathy and diabetic foot. K E Y W O R D Sdiabetic foot, glycaemia, insulin treatment, nephropathy, obesity | 1093 GARCÍA-JACOBO et Al.

Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.