In this work, a novel series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated in vitro on Trypanosoma cruzi trypomastigotes and Leishmania mexicana promastigotes, and cytotoxicity activity in murine macrophages was tested. In silico molecular docking simulations of trypanothione reductase were also done. Three compounds of 33 quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better anti-T. cruzi activity than nifurtimox and beznidazole; two compounds had better anti-leishmanial activity that amphotericin-B, and two compounds showed better activity against both parasites than reference drugs. Compounds M2, M7, M8 and E5, showed low cytotoxic activity on the host cell. The in silico studies suggest that compound M2 is a potential trypanothione reductase inhibitor.

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 A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a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.

Background: Parasitic diseases caused by protozoa such as Chagas disease, leishmaniasis, malaria, African trypanosomiasis, amebiasis, trichomoniasis, and giardiasis are considered serious public health problems in developing countries. Drug-resistance among parasites justifies the search for new therapeutic drugs and the identification of new targets becomes a valuable approach. In this scenario, glycolysis pathway which consists of the conversion of glucose into pyruvate plays an important role in the protozoa energy supply and it is therefore considered as a promising target. In this pathway, triose phosphate isomerase (TIM) plays an essential role in efficient energy production. Furthermore, protozoa TIM show structural differences with human enzyme counterparts suggesting the possibility of obtaining selective inhibitors. Therefore, TIM is considered a valid approach to develop new antiprotozoal agents, inhibiting the glycolysis in the parasite. Objective: In this review, we discuss the drug design strategies, structure-activity relationship, and binding modes of outstanding TIM inhibitors against Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, Giardia lamblia, Leishmania mexicana, Trichomonas vaginalis, and Entamoeba histolytica. Results: TIM inhibitors showed mainly aromatic systems and symmetrical structure, where the size and type of heteroatom are important for enzyme inhibition. This inhibition is mainly based on the interaction with i) the interfacial region of TIM inducing changes on the quaternary and tertiary structure or ii) with the TIM catalytic region were the main pathways that disabled the catalytic activity of the enzyme. Conclusion: Benzothiazole, benzoxazole, benzimidazole, and sulfhydryl derivatives stand out as TIM inhibitors. In silico and in vitro studies demonstrate that the inhibitors bind mainly at the TIM dimer interface. In this review, the development of new TIM inhibitors as antiprotozoal drugs is demonstrated as an important pharmaceutical strategy that may lead to new therapies for these ancient parasitic diseases.

Composite films of chitosan, fish gelatin and microbial transglutaminase (MTgase) were developed. Films were produced by the casting method and dried at room temperature for 30 h, conditioned for 7 days at 30 °C at a relative humidity (RH) from 11 to 90%, and characterized. Chitosan:fish gelatin films in different proportions (100:0, 75:25, 50:50) with MTgase, were subjected to tensile properties and water vapor transmission (WVT) testing. The results showed that tensile strength decreased with an increase in RH and with an increase in gelatin content. Percent of elongation also increased with increasing RH and gelatin concentration. Water vapor transmission showed an increase proportional to an increase in RH with the presence of gelatin being unfavorable for reducing WVT. Results in this work allowed studying the effect of relative humidity on tensile and water vapor properties of chitosan and fish gelatin films.Keywords: biodegradable films; tensile and water vapor properties; enzymatic cross-linking.Practical Application: Assessment of tensile and water vapor properties of biopolymeric films made from chitosan and gelatin.

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