In vitro evaluation of 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against replicative and infective stages of Trypanosoma cruzi.

Current treatment of Chagas disease (CD) is based on two substances, nifurtimox (NT) and benzonidazole (BZ), both considered unsatisfactory mainly due to their low activities and high toxicity profile. One of the main challenges faced in CD management concerns the identification of new drugs active in the acute and chronic phases and with good pharmacokinetic profiles. In this work, we studied the bioactivity of twenty 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against Trypanosoma cruzi epimastigotes and trypomastigotes. We identified seven derivatives with promising activity against epimastigote forms with IC50 values ranging from 6 µM to 44 µM. Most of the compounds showed no significant toxicity against murine macrophages. Our initial investigation on the mechanism of action indicates that this series of compounds may exert their anti-parasitic effect, inducing cell membrane damage. The results in trypomastigotes showed that one derivative, PDAN 78, satisfactorily inhibited metabolic alteration at all concentrations. Moreover, we used molecular modeling to understand how tridimensional and structural aspects might influence the observed bioactivities. Finally, we also used in silico approaches to assess the potential pharmacokinetic and toxicological properties of the most active compounds. Our initial results indicate that this molecular scaffold might be a valuable prototype for novel and safe trypanocidal compounds.

Synthetic molecules as P2X7 receptor antagonists: A medicinal chemistry update focusing the therapy of inflammatory diseases.

Stimulation of the P2X7 receptor by extracellular adenosine 5'-triphosphate induces a series of responses in the organism, exceptionally protein cascades related to the proinflammatory process. This has made P2X7 a target for research on inflammatory diseases such as rheumatoid arthritis. Thus, the incessant search for new prototypes that aim to antagonize the action of P2X7 has been remarkable in recent decades, a factor that has already led to numerous clinical studies in humans. In this review, we present the key molecules developed over the years with potential inhibition of P2X7 and inflammation. In addition, an update with newly developed chemical classes with promising activity and results in clinical studies for human pathologies focusing on P2X7 inhibition.

Inclusion complex of O-allyl-lawsone with 2-hydroxypropyl-ß-cyclodextrin: Preparation, physical characterization, antiparasitic and antifungal activity.

The subclass naphthoquinone represents a substance group containing several compounds with important activities against various pathogenic microorganisms. Accordingly, we evaluated O-allyl-lawsone (OAL) antiparasitic and antifungal activity free and encapsulated in 2-hydroxypropyl-ß-cyclodextrin (OAL MKN) against Trypanosoma cruzi and Sporothrix spp. OAL and OAL MKN were synthesized and characterized by physicochemical methods. The IC50 values of OAL against T. cruzi were 2.4 µM and 96.8 µM, considering epimastigotes and trypomastigotes, respectively. At the same time, OAL MKN exhibited a lower IC50 value (0.5 µM) for both trypanosome forms and low toxicity for mammalian cells. Additionally, the encapsulation showed a selectivity index approximately 240 times higher than that of benznidazole. Regarding antifungal activity, OAL and OAL MKN inhibited Sporothrix brasiliensis growth at 16 µM, while Sporothrix schenckii was inhibited at 32 µM. OAL MKN also exhibited higher selectivity toward fungus than mammalian cells. In conclusion, we described the encapsulation of O-allyl-lawsone in 2-hydroxypropyl-ß-cyclodextrin, increasing the antiparasitic activity compared with the free form and reducing the cytotoxicity and increasing the selectivity towardSporothrix yeasts and the T. cruzi trypomastigote form. This study highlights the potential development of this inclusion complex as an antiparasitic and antifungal agent to treat neglected diseases.

Influence of purinergic signaling on glucose transporters: A possible mechanism against insulin resistance?

Metabolic disorders, such as insulin resistance, affect many people worldwide due to the prevalence of obesity and type 2 diabetes, which are pathologies that impair glycemic metabolism. Glucose is the primary energetic substrate of the body and is essential for cellular function. As the cell membrane is not permeable to glucose molecules, there are two distinct groups of glucose transporters: sodium-glucose-linked transporters (SGLTs) and the glucose transporter (GLUT) family. These transporters facilitate the entry of glucose into the bloodstream or cytoplasm where it functions in the production of adenosine 5 ́-triphosphate (ATP). This nucleotide acts in several cellular mechanisms, such as protein phosphorylation and cellular immune processes. ATP directly and indirectly acts as an agonist for purinergic receptors in high concentrations in the extracellular environment. Composed by P1 and P2 groups, the purinoreceptors cover several cellular mechanisms involving cytokines, tumors, and metabolic signaling pathways. Previous publications have indicated that the purinergic signaling activity in insulin resistance and glucose transporters modulates relevant actions on the deregulations that can affect glycemic homeostasis. Thus, this review focuses on the pharmacological influence of purinergic signaling on the modulation of glucose transporters, aiming for a new way to combat insulin resistance and other metabolic disorders.