Assessment of the Activity of Nitroisoxazole Derivatives against .

The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds' lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of , with a 52 ± 4% trypanocidal effect for compound .

Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity.

Purpose: Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a highly heterogeneous syndrome with distinct phenotypes that impact immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct functional phenotypes of immune cells.

A new strategy to build electrochemical enzymatic biosensors using a nanohybrid material based on carbon nanotubes and a rationally designed schiff base containing boronic acid.

We report a nanohybrid material obtained by non-covalent functionalization of multi-walled carbon nanotubes (MWCNTs) with the new ligand (((1E,1'E)-(naphthalene-2,3-diylbis(azaneylylidene))bis(methaneylylidenedene)) bis(4-hydroxy-3,1-phenylene))diboronic acid (SB-dBA), rationally designed to mimic some recognition properties of biomolecules like concanavalin A, for the development of electrochemical biosensors based on the use of glycobiomolecules as biorecognition element. We present, as a proof-of-concept, a hydrogen peroxide biosensor obtained by anchoring horseradish peroxidase (HRP) at a glassy carbon electrode (GCE) modified with the nanohybrid prepared by sonication of 2.0 mg mL MWCNTs and 0.

Side Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator.

The quinuclidine scaffold has been extensively used for the development of nicotinic acetylcholine receptor (nAChR) agonists, with hydrophobic substituents at position 3 of the quinuclidine framework providing selectivity for α7 nAChRs. In this study, six new ligands (-) containing a 3-(pyridin-3-yloxy)quinuclidine moiety (ether quinuclidine) were synthesized to gain a better understanding of the structural-functional properties of ether quinuclidines. To evaluate the pharmacological activity of these ligands, two-electrode voltage-clamp and single-channel recordings were performed.

-Arylation of 3-Formylquinolin-2(1)-ones Using Copper(II)-Catalyzed Chan-Lam Coupling.

3-formyl-2-quinolones have attracted the scientific community's attention because they are used as versatile building blocks in the synthesis of more complex compounds showing different and attractive biological activities. Using copper-catalyzed Chan-Lam coupling, we synthesized 32 new -aryl-3-formyl-2-quinolone derivatives at 80 °C, in air and using inexpensive phenylboronic acids as arylating agents. 3-formyl-2-quinolones and substituted 3-formyl-2-quinolones can act as substrates, and among the products, the -methyl derivative was used as a substrate to obtain different derivatives such as alcohol, amine, nitrile, and chalcone.

Field Tests of Three Alternative Insecticides with Protein Bait for the Development of an Insecticide Rotation Program to Control Melon Flies, (Coquillett) (Diptera: Tephritidae).

High levels of resistance to the spinosad-based insecticidal protein bait GF-120 have been detected in some populations of melon fly, (Coquillett) (Diptera: Tephritidae), in Hawaii in 2017. To provide cucurbit farmers in Hawaii with alternative insecticides, we field-tested the effectiveness of Agri-Mek SC (a.i.

Omics of endothelial cell dysfunction in sepsis.

During sepsis, defined as life-threatening organ dysfunction due to dysregulated host response to infection, systemic inflammation activates endothelial cells and initiates a multifaceted cascade of pro-inflammatory signaling events, resulting in increased permeability and excessive recruitment of leukocytes. Vascular endothelial cells share many common properties but have organ-specific phenotypes with unique structure and function. Thus, therapies directed against endothelial cell phenotypes are needed to address organ-specific endothelial cell dysfunction.

Synthesis of -Arylcytisine Derivatives Using the Copper-Catalyzed Chan-Lam Coupling.

-Arylcytisine derivatives are quite rare. We report here a practical methodology to obtain these compounds. Using the copper-catalyzed Chan-Lam coupling, we synthesized new -arylcytisine derivatives at room temperature, in air and using inexpensive phenylboronic acids.

Supramolecular Control of Reactivity toward Hydrolysis of 7-Diethylaminocoumarin Schiff Bases by Cucurbit[7]uril Encapsulation.

A series of aromatic Schiff bases, featuring 7-diethylamino-coumarin and with five different substituents at an adjacent phenyl ring, were synthesized and characterized. With the aim of assessing the stability of these dyes in acidic medium, their hydrolysis reactions were kinetically studied in the absence and presence of the macrocycle cucurbit[7]uril (CB[7]). Our results are consistent with a model containing three different forms of substrates (un-, mono-, and diprotonated) and three parallel reaction pathways.

Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, I, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations).

Sex-Dependent Differences in Physical Exercise-Mediated Cognitive Recovery Following Middle Cerebral Artery Occlusion in Aged Rats.

Stroke remains a leading cause of death and disability in the United States. No current treatments exist to promote cognitive recovery in survivors of stroke. A previous study from our laboratory determined that an acute bout of forced treadmill exercise was able to promote cognitive recovery in 3 month old male rats after middle cerebral artery occlusion (MCAo).

Synthesis of β-alkoxy--protected phenethylamines one-pot copper-catalyzed aziridination and ring opening.

A regioselective, copper-catalyzed, one-pot aminoalkoxylation of styrenes using primary and secondary alcohols and three different iminoiodanes as alkoxy and nitrogen sources respectively, is reported. The β-alkoxy--protected phenethylamines obtained were used to synthesise β-alkoxy--benzylphenethylamines which are interesting new compounds that could act as possible neuronal ligands.

Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors.

The α7 nicotinic acetylcholine receptor (nAChR) is expressed in neuronal and non-neuronal cells and is involved in several physiopathological processes, and is thus an important drug target. We have designed and synthesized novel piperidine derivatives as α7 nAChR antagonists. Thus, we describe here a new series of 1-[2-(4-alkoxy-phenoxy-ethyl)]piperidines and 1-[2-(4-alkyloxy-phenoxy-ethyl)]-1-methylpiperidinium iodides (compounds and ), and their actions on α7 nAChRs.

Characterization of a Novel Drosophila SERT Mutant: Insights on the Contribution of the Serotonin Neural System to Behaviors.

A better comprehension on how different molecular components of the serotonergic system contribute to the adequate regulation of behaviors in animals is essential in the interpretation on how they are involved in neuropsychiatric and pathological disorders. It is possible to study these components in "simpler" animal models including the fly Drosophila melanogaster, given that most of the components of the serotonergic system are conserved between vertebrates and invertebrates. Here we decided to advance our understanding on how the serotonin plasma membrane transporter (SERT) contributes to serotonergic neurotransmission and behaviors in Drosophila.

Physical Exercise Improves Cognitive Outcomes in 2 Models of Transient Cerebral Ischemia.

Background And Purpose: Preclinical studies suggest that exercise can enhance cognition after cerebral ischemia but often use long training regiments and test cognition during or acutely after training. The cognitive changes may result from enhanced physical fitness and may only provide acute benefit. We sought to determine whether a short period of exercise after cerebral ischemia could improve cognitive outcomes when measured days after completion of exercise training in 2 cerebral ischemia models.

Regioselective Intermolecular Diamination and Aminooxygenation of Alkenes with Saccharin.

Palladium catalysis enables the regioselective difunctionalization of alkenes using saccharin as the nitrogen source in the initial step of aminopalladation. Depending on the reaction conditions, diamination or aminooxygenation pathways can be accessed using hypervalent iodine reagents as the terminal oxidants. The aminooxygenation of allylic ethers originates from an unprecedented ambident behavior of saccharin.

Dual effects of a 2-benzylquinuclidinium derivative on α7-containing nicotinic acetylcholine receptors in rat hippocampal interneurons.

Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the brain. Particularly α7-containing nAChRs, associated with several physiological roles and pathologies, are one of the most abundant. Here, we studied 2-(4-hexyloxybenzyl)-1-methylquinuclidin-1-ium iodide (designated as 8d), on ion currents elicited by choline, ICh, (Ch, a selective agonist for α7-containing nAChRs), recorded in interneurons from the stratum radiatum of the rat hippocampal CA1 region by using the whole-cell voltage-clamp technique.

The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors in Mice.

Background: Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective α7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative α7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice.

Copper-catalyzed intermolecular and regioselective aminofluorination of styrenes: facile access to β-fluoro-N-protected phenethylamines.

A copper-catalyzed regio- and intermolecular aminofluorination of styrenes has been developed. In this reaction Ph-I=N-Ts and Et3N·3HF act as nitrogen and fluorine sources, respectively. The obtained β-fluoro-N-Ts-phenethylamines can be N-alkylated with subsequent deprotection affording the corresponding β-fluoro-N-alkylated phenethylamines, which are interesting building blocks for compounds acting on neuronal targets.

Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor.

Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species.

Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms.

This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca(2+) influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed.

Further mulinane diterpenoids from Azorella compacta.

Objectives: The chemical study of a dichloromethane extract from Azorella compacta was directed to the isolation of characteristic mulinane and azorellane diterpenoids in order to determine their gastroprotective activity.

Methods: Usual chromatographic techniques on the extract led to the isolation of 12 compounds, which were identified by their spectroscopic properties. The HCl/ethanol-induced gastric lesions model in mice was used to determine the gastroprotective activity.

Why is quercetin a better antioxidant than taxifolin? Theoretical study of mechanisms involving activated forms.

The stronger antioxidant capacity of the flavonoid quercetin (Q) compared with taxifolin (dihydroquercetin, T) has been the subject of previous experimental and theoretical studies. Theoretical work has focused on the analysis of hydrogen bond dissociation energies (BDE) of the OH phenolic groups, but consider mechanisms that only involve the transfer of one hydrogen atom. In the present work we consider other mechanisms involving a second hydrogen transfer in reactions with free radicals.

Synthesis and antiplasmodial activity of some 1-azabenzanthrone derivatives.

Some synthetic 1-azabenzanthrones (7H-dibenzo[de,h]quinolin-7-ones) are weakly to moderately cytotoxic, suggesting that they might also show antiparasitic activity. We have now tested a small collection of these compounds in vitro against a chloroquine-resistant Plasmodium falciparum strain, comparing their cytotoxicity against normal human fibroblasts. Our results indicate that 5-methoxy-1-azabenzanthrone and its 2,3-dihydro analogue have low micromolar antiplasmodial activities and showed more than 10-fold selectivity against the parasite, indicating that the dihydro compound, in particular, might serve as a lead compound for further development.