Structure-activity relationships of novel N-imidazoylpiperazines with potent anti-Trypanosoma cruzi activity.

Background: Chagas disease is caused by the parasite Trypanosoma cruzi, and the lack of effective and safe treatments makes identifying new classes of compounds with anti-T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N-imidazoylpiperazine was performed. Results: Compound 2, a piperazine derivative active against T. cruzi, was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.

DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years, there has been an excessive growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of ageassociated neurodegeneration, including Alzheimer-type pathology. OBJECTIVE: In this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents. METHODS: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data. RESULTS: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. CONCLUSION: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.

Monomethylsulochrin isolated from biomass extract of Aspergillus sp. against Leishmania amazonensis: In vitro biological evaluation and molecular docking.

Leishmaniasis represents a serious world health problem, with 1 billion people being exposed to infection and a broad spectrum of clinical manifestations with a potentially fatal outcome. Based on the limitations observed in the treatment of leishmaniasis, such as high cost, significant adverse effects, and the potential for drug resistance, the aim of the present study was to evaluate the leishmanicidal activity of the compounds pseurotin A and monomethylsulochrin isolated from the biomass extract of Aspergillus sp. The chromatographic profiles of the extract were determined by high-performance liquid chromatography coupled with a diode-array UV-Vis detector (HPLC-DAD-UV), and the molecular identification of the pseurotin A and monomethylsulochrin were carried out by electrospray ionization mass spectrometry in tandem (LC-ESI-MS-MS) and nuclear magnetic resonance (NMR). Antileishmanial activity was assayed against promastigote and intracellular amastigote of Leishmania amazonensis. As a control, cytotoxicity assays were performed in non-infected BALB/c peritoneal macrophages. Ultrastructural alterations in parasites were evaluated by transmission electron microscopy. Changes in mitochondrial membrane potential were determined by flow cytometry. Only monomethylsulochrin inhibited the promastigote growth (IC50 18.04 ± 1.11 µM), with cytotoxicity to peritoneal macrophages (CC50 5.09 91.63 ± 1.28 µM). Activity against intracellular amastigote forms (IC50 5.09 ± 1.06 µM) revealed an increase in antileishmanial activity when compared with promastigotes. In addition to a statistically significant reduction in the evaluated infection parameters, monomethylsulochrin altered the ultrastructure of the promastigote forms with atypical vacuoles, electron-dense corpuscles in the cytoplasm, changes at the mitochondria outer membrane and abnormal disposition around the kinetoplast. It was showed that monomethylsulochrin leads to a decrease in the mitochondrial membrane potential (25.9%, p = 0.0286). Molecular modeling studies revealed that monomethylsulochrin can act as inhibitor of sterol 14-alpha-demethylase (CYP51), a therapeutic target for human trypanosomiasis and leishmaniasis. Assessed for its drug likeness, monomethylsulochrin follows the Lipinski Rule of five and Ghose, Veber, Egan, and Muegge criteria. Furthermore, monomethylsulochrin can be used as a reference in the development of novel and therapeutically useful antileishmanial agents.

Witches, potions, and metabolites: an overview from a medicinal perspective.

Witches were popularly imagined as older women (above middle age), with large warty noses, whose clothes were shabby and used pointy hats. They are usually associated with a cauldron and the presence of a black cat that accompany them in this imagery projection. The fact is that, historically, many women have suffered countless physical and emotional acts of violence, for which different analysis can be made from the perspective of the Human Sciences. Of the historical narratives that deal with this violence, the Salem witch trials stand out as the biggest witch hunt in history, where a series of hearings and trials of people accused of witchcraft took place in colonial Massachusetts, between February 1693 and May of 1694, episodes in which more than two hundred people were accused of practices of heresy. However, it is necessary to recognize that many of these women considered witches were, in fact, profound connoisseurs of plant species with biological properties, even though there was not precise information about the active compounds of these plants. With the development of characterization techniques for organic compounds, like spectrometric and spectroscopic analyses, most of the metabolites present in the "potions" had their structures elucidated, allowing a more appropriate knowledge of the possible metabolic pathways. In this article, we report a study of the structure-activity relationships for two of the most famous potions in history: the sleep potion and the love potion, with the aim of presenting new discussions within the scope of medicinal chemistry that can contribute to the process of science diffusion.

Carajurin Induces Apoptosis in Leishmania amazonensis Promastigotes through Reactive Oxygen Species Production and Mitochondrial Dysfunction.

Carajurin is the main constituent of Arrabidaea chica species with reported anti-Leishmania activity. However, its mechanism of action has not been described. This study investigated the mechanisms of action of carajurin against promastigote forms of Leishmania amazonensis. Carajurin was effective against promastigotes with IC50 of 7.96 ± 1.23 µg.mL-1 (26.4 µM), and the cytotoxic concentration for peritoneal macrophages was 258.2 ± 1.20 µg.mL-1 (856.9 µM) after 24 h of treatment. Ultrastructural evaluation highlighted pronounced swelling of the kinetoplast with loss of electron-density in L. amazonensis promastigotes induced by carajurin treatment. It was observed that carajurin leads to a decrease in the mitochondrial membrane potential (p = 0.0286), an increase in reactive oxygen species production (p = 0.0286), and cell death by late apoptosis (p = 0.0095) in parasites. Pretreatment with the antioxidant NAC prevented ROS production and significantly reduced carajurin-induced cell death. The electrochemical and density functional theory (DFT) data contributed to support the molecular mechanism of action of carajurin associated with the ROS generation, for which it is possible to observe a correlation between the LUMO energy and the electroactivity of carajurin in the presence of molecular oxygen. All these results suggest that carajurin targets the mitochondria in L. amazonensis. In addition, when assessed for its drug-likeness, carajurin follows Lipinski''s rule of five, and the Ghose, Veber, Egan, and Muegge criteria.

Synthesis of chalcones derived from 1-naphthylacetophenone and evaluation of their cytotoxic and apoptotic effects in acute leukemia cell lines.

Chalcones and their derivatives have been described as promising compounds with antiproliferative activity against leukemic cells. This study aimed to investigate the cytotoxic effect of three synthetic chalcones derived from 1-naphthylacetophenone (F07, F09, and F10) in acute leukemia cell lines (K562 and Jurkat) and examine the mechanisms of cell death induced by these compounds. The three compounds were cytotoxic to K562 and Jurkat cells, with IC50 values ranging from 1.03 to 31.66 µM. Chalcones induced intrinsic and extrinsic apoptosis, resulting in activation of caspase-3 and DNA fragmentation. F07, F09, and F10 were not cytotoxic to human peripheral blood mononuclear cells, did not produce any significant hemolytic activity, and did not affect platelet aggregation after ADP stimulation. These results, combined with calculations of molecular properties, suggest that chalcones F07, F09, and F10 are promising molecules for the development of novel antileukemic drugs.

Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

Five synthetic sulfonamides derived from carvacrol, a natural product and a small molecule with druglike properties, were evaluated with respect to their effects on the cognitive deficits of animals with streptozotocin (STZ)-induced Alzheimer's disease (AD). Memory, ambulation, anxiety and oxidative stress were evaluated. In vitro assays were performed to assess the inhibition of acetylcholinesterase (AChE), and the data were combined with molecular docking for the establishment of structure-activity relationships. The memories of animals treated with the compounds derived from morpholine (1), hydrazine (3) and 2-phenol (5) were improved. Compound 3 was the most promising, yielding excellent results in the inhibitory avoidance test. Moreover, the compounds did not exhibit any deleterious effects on the animals' ambulation in the open field test. Molecular docking confirmed the results obtained in the AChE inhibition assay. In short, compounds 1, 3 and 5 can reduce STZ-induced deficits and show potential for the treatment of Alzheimer's. In addition, these agents produce significant anxiolytic and antioxidant effects.