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1-(7-Chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) is a new multi-target directed ligand (MTDL) rationally designed to have affinity with β-secretase (BACE), Glycogen Synthase Kinase 3β (GSK3β) and acetylcholinesterase, which are considered promising targets on the development of disease-modifying therapies against Alzheimer's Disease (AD). Previously, QTC-4-MeOBnE treatment showed beneficial effects in preclinical AD-like models by influencing in vivo neurogenesis, oxidative and inflammatory pathways. However, the biological effect and mechanism of action exerted by QTC-4-MeOBnE in AD cellular models have not been elucidated yet. Hereby we investigate the acute effect of QTC-4-MeOBnE on neuronal cells overexpressing Amyloid Protein Precursor (APP) or human tau protein, the two main features of the AD pathophysiology. When compared to the control group, QTC-4-MeOBnE treatment prevented amyloid beta (Aβ) formation through the downregulation of APP and BACE levels in APPswe-expressing cells. Furthermore, in N2a cells overexpressing human tau, QTC-4-MeOBnE reduced the levels of phosphorylated forms of tau via the modulation of the GSK3β pathway. Taken together, our findings provide new insights into the mechanism of action exerted by QTC-4-MeOBnE in AD cellular models, and further support its potential as an interesting therapeutic strategy against AD.

Sulfamoyl-triazolyl-carboxamides were synthesized using DBU as a catalyst, and their molecular docking and MPO activity analyses were performed.

Hypothyroidism is a condition that affects multiple systems, including the central nervous system, causing, for example, cognitive deficits closely related to Alzheimer's disease. The flavonoid chrysin is a natural compound associated with neuronal improvement in several experimental models. Here, we evaluated the effect of chrysin on cognitive impairment in hypothyroid female mice by exploring neuroplasticity. Hypothyroidism was induced by continuous exposure to 0.1% methimazole (MTZ) in drinking water for 31 days. On the 32nd day, the animals showed low plasma levels of thyroid hormones (hypothyroid mice) than the control group (euthyroid mice). Subsequently, mice were intragastrically administered with vehicle or chrysin (20 mg/kg) once a day for 28 consecutive days. At the end of the treatments, behavioral tests were performed: open-field test (OFT) and morris water maze (MWM). Then, the levels of neurotrophins (BDNF and NGF) in the hippocampus and prefrontal cortex were measured and tested the affinity of chrysin with neurotrophinergic receptors through molecular docking. Hypothyroid mice showed memory deficit in the MWM and reduced neurotrophins levels in the hippocampus and prefrontal cortex, meanwhile, the chrysin treatment was able to reversed the deficit of spatial memory function and increased the levels of BDNF in hipocamppus and NGF in both structures. Additionally, molecular docking analysis showed that chrysin potentially binds to the active site of the TrkA, TrkB, and p75NTR receptors. Together, these findings suggest that chrysin reversed behavioral and neurochemical alterations associated with memory deficit induced by hypothyroidism, possibly by modulating synaptic plasticity in the neurotrophinergic system.

Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to β-secretase (BACE), glycogen synthase kinase 3β (GSK3β), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1 mg/kg) administration for 45 days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aβ) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.

Alzheimer’s disease (AD) is a worldwide problem, and there are currently no treatments that can stop this disease. To investigate the binding affinity of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) with acetylcholinesterase (AChE), to verify the effects of FSP in an AD model in mice and to evaluate the toxicological potential of this compound in mice. The binding affinity of FSP with AChE was investigated by molecular docking analyses. The AD model was induced by streptozotocin (STZ) in Swiss mice after FSP treatment (1 mg/kg, intragastrically (i.g.)), 1st-10th day of the experimental protocol. Anxiety was evaluated in an elevated plus maze test, and memory impairment was evaluated in the Y-maze, object recognition and step-down inhibitory avoidance tasks. The cholinergic system was investigated based on by looking at expression and activity of AChE and expression of choline acetyltransferase (ChAT). We evaluated expression and activity of Na+/K+-ATPase. For toxicological analysis, animals received FSP (300 mg/kg, i.g.) and aspartate aminotransferase, alanine aminotransferase activities were determined in plasma and δ-aminolevulinate dehydratase activity in brain and liver. FSP interacts with residues of the AChE active site. FSP mitigated the induction of anxiety and memory impairment caused by STZ. FSP protected cholinergic system dysfunction and reduction of activity and expression of Na+/K+-ATPase. FSP did not modify toxicological parameters evaluated and did not cause the death of mice. FSP protected against anxiety, learning and memory impairment with involvement of the cholinergic system and Na+/K+-ATPase in these actions.

We describe our results for the synthesis of 2′-(1,2,3-triazoyl)-acetophenones by copper catalyzed azide–alkyne cycloaddition of 2′-azidoacetophenone with alkynes. The corresponding 2′-(1,2,3-triazoyl)-acetophenones were obtained in moderate to excellent yields and according to our experiments, it was observed that ultrasound accelerates the reaction compared to conventional heating. In addition, the obtained compounds were screened by molecular docking for their possible inhibitory effect on the activity of monoamine oxidase (MAO), an enzyme responsible for the degradation of monoamine neurotransmitters. Three compounds were selected and presented an inhibitory effect on both MAO-A and B isoform activities in vitro. These new MAO inhibitors may be of interest to treat monoamine deficit related-neuropsychiatric disorders, such as depression and Parkinson's disease.

Growing evidence suggests that drugs targeting neurogenesis and myelinization could be novel therapeutic targets against Alzheimer's disease (AD). Intracerebroventricular (icv) injection of streptozotocin (STZ) induces neurodegeneration through multiple mechanisms ultimately resulting in reduced adult neurogenesis. Previously, the multitarget compound QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide) demonstrated beneficial effects in preclinical models of AD. Here we investigated its pharmacokinetics profile and the effect on memory impairments and neurodegeneration induced by STZ. Two icv injections of STZ resulted in significant cognitive and memory impairments, assessed by novel object recognition, Y-maze, social recognition, and step-down passive avoidance paradigms. These deficits were reversed in STZ-injected mice treated with QTC-4-MeOBnE. This effect was associated with reversion of neuronal loss in hippocampal dentate gyrus, reduced oxidative stress, and amelioration of synaptic function trough Na+/K+ ATPase and acetylcholinesterase activities. Furthermore, brains from QTC-4-MeOBnE-treated mice had a significant increase in adult neurogenesis and remyelination through Prox1/NeuroD1 and Wnt/β-catenin pathways. Overall, our findings support the potential anti-AD effect of QTC-4-MeOBnE through multiple pathways, all of which have been involved in the onset and progression of the disease.

Major depressive disorder (MDD) is a chronic mental illness affecting a wide range of people worldwide. The pathophysiology of MDD is not completely elucidated, but it is believed that oxidative stress and neuroinflammation are involved. In light with this, the aim of the present study was to investigate whether a single administration of the antioxidant 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) was able to reverse the streptozotocin-induced depression-like behavior, oxidative stress, and neuroinflammation in mice. MFSeI (10 mg/kg) was administered intragastrically (i.g.) 24 h after the intracerebroventricular injection of STZ (0.2 mg/4 μL/per mouse). Thirty minutes after MFSeI administration, behavioral tests and neurochemical analyses were performed. Fluoxetine (10 mg/kg, i.g.) was used as a positive control. MFSeI and fluoxetine were able to reverse the STZ-induced depression-like behavior, as evidenced by decreased immobility time in the forced swimming test and increased grooming time in the splash test. Mechanistically, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortices and hippocampi of STZ-treated mice. Additionally, neuroinflammation (i.e. expression of NF-κB, IL-1β, and TNF-α) and the reduced mRNA levels of BDNF in the and hippocampi of depressed mice were reversed by treatment with MFSeI. Fluoxetine did not improve the STZ-induced alterations at the levels of reactive species, NF-κB and BDNF in the prefrontal cortices neither the levels of TNF-α in both brain regions. Together, these data suggest that the MFSeI may be a promising compound with antidepressant-like action, reducing oxidative stress and modulating inflammatory pathways in the brain of depressed mice.

We described here our results on the use of thiourea as a ligand in the copper catalysed azide-alkyne cycloaddition (CuAAC) of 2-azidobenzaldehyde with alkynes. Reactions were performed reacting 2-azidobenzaldehyde with a range of terminal alkynes using 10 mol % of copper iodide as a catalyst, 20 mol % of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 °C under nitrogen atmosphere. The corresponding 2-(1H-1,2,3-triazoyl)-benzaldehydes (2-TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: β-secretase (BACE), glycogen synthase kinase (GSK-3β) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5 a (2-(4-phenyl-1H-1,2,3-triazol-1-yl)benzaldehyde), 5 b (2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)benzaldehyde), and 5 d (2-(4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde) were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation. Due the antioxidant potential ally to the affinity with BACE, GSK-3β and AChE, compound 5 b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5 b (1 mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK-3β expression.

A range of bis-triazolylchalcogenium-BTD 3 was synthesized by a copper-catalyzed azide-alkyne cycloaddition of azido arylchalcogenides 1 and 4,7-diethynylbenzo[c][1,2,5]thiadiazole 2. Eight new compounds were obtained in moderate to good yields using 1 mol % of copper(II) acetate monohydrate under mild reaction conditions. In addition, the synthesized bis-triazolylchalcogenium-BTD 3a-3h were investigated regarding their photophysical, electrochemical, and biomolecule binding properties in solution. In general, compounds presented strong absorption bands at the 250-450 nm region and cyan to green emission properties. The redox process attributed to the chalcogen atom was observed by electrochemical analysis (CV techniques). In addition, spectroscopic studies by UV-vis, steady-state emission fluorescence, and molecular docking calculations evidenced the ability of each derivative to establish interactions with calf-thymus DNA (CT-DNA) and bovine serum albumin (BSA). The behavior presented for this new class of compounds makes them a promising tool as optical sensors for biomolecules.

Four new hybrid molecules containing benzo-2,1,3-thiadiazole, benzofuran and arylselanyl moieties, named 4,7-bis(3-(arylselanyl)benzofuran-2-yl)benzo[c][1,2,5]thiadiazoles, were designed and synthesized in good yields through an electrophilic cyclization of 4,7-bis((2-methoxyphenyl)ethynyl)benzo[c][1,2,5]thiadiazole 1 and diaryl diselenides 2 using trichloroisocyanuric acid to generate electrophilic arylselanyl species. The photophysical properties of compounds 3a–d were investigated using UV-vis absorption and emission fluorescence analysis. The emission fluorescence analysis showed a yellow-orange region emission. Large Stokes shift values were observed for all new derivatives and attributed to the ICT state and to the electron-substituent properties. The biomolecule-binding DNA and HSA-binding interactions were also investigated by experimental and theoretical methods.

In the present study, the antitumoral properties of a series of 7-chloroquinoline-1,2,3-triazoyl-carboxamides (QTCA) were investigated by analyzing their cytotoxic activities against human bladder cells (5637; grade II carcinoma). In addition, their effects on cell viability, cell cycle arrest mechanisms, apoptosis induction, in silico molecular docking, and detection of pro-apoptotic and anti-apoptotic proteins were evaluated. The cytotoxicity assay identified major dose- and time-dependent cytotoxic effects in 5637 cells after they were exposed to treatment with QTCA, only minimal effects were observed on normal cells. A live/dead assay confirmed that significant cell death, arrest in the G0/G1 phase and apoptosis were associated with treatment by 1-(7-Chloroquinolin-4-yl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (QTCA-1) and 1-(7-Chloroquinolin-4-yl)-N-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (QTCA-4). The in silico results indicated that these compounds acted through different mechanisms for the induction of cell cycle arrest and apoptosis. Western blotting confirmed the binding of the QTCAs to pro- and anti-apoptotic proteins. In conclusion, QTCA-1 and QTCA-4 are promising candidates for inducing cytotoxicity, cell cycle arrest, and apoptosis in human bladder cancer cells.

Clinical and preclinical investigations have suggested a possible biological link between major depressive disorder (MDD) and Alzheimer’s disease (AD). Therefore, a pharmacologic approach to treating MDD could be envisioned as a preventative therapy for some AD cases. In line with this, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide (QTC-4-MeOBnE) is characterized as an inhibitor of β-secretase, glycogen synthase kinase 3β, and acetylcholinesterase and has also shown secondary effects underlying the modulation of neurogenesis and synaptic plasticity pathways. Therefore, we investigated the effects of QTC-4-MeOBnE treatment (0.1 or 1 mg/kg) on depressive-like behavior and cognitive impairments elicited by repeated injections of lipopolysaccharide (LPS; 250 μg/kg) in mice. Injections of LPS for seven days led to memory impairments and depressive-like behavior, as evidenced in the Y-maze/object recognition test and forced swimming/splash tests, respectively. However, these impairments were prevented in mice that, after the last LPS injection, were also treated with QTC-4-MeOBnE (1 mg/kg). This effect was associated with restoring blood-brain barrier permeability, reducing oxidative/nitrosative biomarkers, and decreasing neuroinflammation mediated NF-κB signaling in the hippocampus and cortex of the mice. To further investigate the involvement with NF-κB signaling, we evaluated the effects of QTC-4-MeOBnE on microglial cell activation through canonical and non-canonical pathways and the modulation of the involved components. Together, our findings highlight the pharmacological benefits of QTC-4-MeOBnE in a mouse model of sickness behavior and memory impairments, supporting the novel concept that since this molecule produces anti-depressant activity, it could also be beneficial for preventing AD onset and related dementias in subjects suffering from MDD through inflammatory pathway modulation.

The present study aimed to investigate the effect of AZT derivates containing tellurium (Te) on human breast cancer cell lines and the mechanisms underlying cell death. The inhibitory effect of AZT and its derivatives (7m and 7r) was determined by the MTT assay (6.25, 12.5, 25, 50 and 100 μM in 24 and 48 h time points), meanwhile the induction of apoptosis and the cell cycle phases was investigated by flow cytometry. The MTT assay showed that AZT derivatives decreased the rate of cell proliferation at concentrations of 12.5 μM, while commercial AZT showed low antitumor potential. In flow cytometric analysis, we demonstrate that the AZT derivatives do not induce apoptosis at the concentration tested and promote the cell cycle arrest in the S phase. Besides, predicted absorption, distribution, metabolization, excretion and toxicity analysis suggest that the compounds possess a good pharmacokinetic profile and possibly less toxicity when compared to conventional AZT. These compounds containing tellurium in their formulation are potential therapeutic agents for breast cancer.

Cognitive decline and memory impairment induced by disruption of cholinergic neurons and oxidative brain damage are among the earliest pathological hallmark signatures of Alzheimer's disease. Scopolamine is a postsynaptic muscarinic receptor blocker which causes impairment of cholinergic transmission resulting in cognitive deficits. Herein we investigated the effect of QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide) on memory impairments in mice chronically treated with scopolamine and the molecular mechanisms involved. Administration of scopolamine (1 mg/kg) for 15 days resulted in significant impairments in working and short-term memory in mice, as assessed by the novel object recognition and the Y-maze paradigms. However, both deficits were prevented if mice receiving the scopolamine were also treated with QTC-4-MeOBnE. This effect was associated with an increase in antioxidant enzymes (superoxide dismutase and catalase), a reduction in lipid peroxidation, and an increase in Nrf2 expression. Moreover, brains from QTC-4-MeOBnE treated mice had a significant decrease in acetylcholinesterase activity and glycogen synthase kinase-3β levels but an increase in brain-derived neurotrophic factor and Bcl-2 expression levels. Taken together our findings demonstrate that the beneficial effect of QTC-4-MeOBnE in a mouse model of scopolamine-induced memory impairment is mediated via the involvement of different molecular pathways including oxidative stress, neuroplasticity, neuronal vulnerability, and apoptosis. Our study provides further evidence on the promising therapeutic potential of QTC-4-MeOBnE as a multifactorial disease modifying drug in AD and related dementing disorders.

The aim of the present study was investigate the binding affinity of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) with acetylcholinesterase (AChE). We also evaluated the effect of MTDZ against scopolamine (SCO)-induced amnesia in mice and we looked at the toxicological potential of this compound in mice. The binding affinity of MTDZ with AChE was investigated by molecular docking analyses. For an experimental model, male Swiss mice were treated daily with MTDZ (10 mg/kg, intragastrically (i.g.)) or canola oil (10 ml/kg, i.g.), and induced, 30 min later, with injection of SCO (0.4 mg/kg, intraperitoneally (i.p.)) or saline (0.9%, 5 ml/kg, i.p.) daily. From day 1 to day 10, mice were submitted to the behavioral tasks (Barnes maze, open-field, object recognition and location, Y-maze and step-down inhibitory avoidance tasks), 30 min after induction with SCO. On the tenth day, the animals were euthanized and blood was collected for the analysis of biochemical markers (creatinine, aspartate (AST), and alanine (ALT) aminotransferase). MTDZ interacts with residues of the AChE active site. SCO caused amnesia in mice by changing behavioral tasks. MTDZ treatment attenuated the behavioral changes caused by SCO. In ex vivo assay, MTDZ also protected against the alteration of AChE activity, reactive species (RS) levels, thiobarbituric acid reative species (TBARS) levels, catalase (CAT) activity in tissues, as well as in transaminase activities of plasma caused by SCO in mice. In conclusion, MTDZ presented anti-amnesic action through modulation of the cholinergic system and provided protection from kidney and liver damage caused by SCO.

Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.

Herein we report the use of ultrasonic irradiation (US) in the synthesis of six new semi-synthetic selenium-containing chrysin derivatives by a simple and effective methodology utilizing CuI as catalyst, in good to excellent yields (60–89%). It was observed that US accelerates the reaction compared to conventional heating with excellent selectivity for diselenylated products. Compounds were tested for their antioxidant and anticancer activities in vitro and it was observed that the presence of selenium in the A-ring of chrysin enhanced both antioxidant and anticancer properties. Semi-synthetic 6,8-bis(o-tolylselanyl)-chrysin 3b has the best radical scavenging activity of DPPH (Imax: 39.79 µM) and ABTS+ (IC50: 6.5 µM) radicals. Similarly, in the Reactive Species (RS) assay, 3b showed high antioxidant activity in mice cortex (IC50: 5.67 µM), whereas 6,8-bis(p-anisoylselanyl)-chrysin 3c was the more active in the hippocampus (IC50: 5.63 µM). The Se-chrysins were effective in prevention of lipid peroxidation, highlighting 6,8-bis(p-fluorophenylselanyl)-chrysin 3d in cortex (IC50: 0.54 µM) and 3b in hippocampus (IC50: 0.27 µM). In addition, 3d was effective in inhibiting human lung adenocarcinoma (A549) cells growth, with a IC50 of 19.9 µM after 72 h of treatment, while 6,8-bis(p-anisoylselanyl)-chrysin 3c presented the higher antiproliferative activity after 48 h of treatment (IC50 of 41.4 µM).

Breast cancer is a major public health burden in both developed and developing countries and there is still a need to screen new molecules with different modes of actions. The aims of this study were to evaluate the selectivity profile, apoptotic cell death and cell cycle arrest induced by 7-chloroquinoline-1,2,3-triazoyl carboxamides derivatives in hormonal-dependent and hormonal-independent breast cancer cells. Results showed significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner after treatment with 7-chloroquinoline derivatives QTCA-1, QTCA-2 and QTCA-3. QTCA-1 displayed the highest cytotoxic activity from all the tested compounds in MDA-MB-231 with IC50 values of 20.60, 20.42 and 19.91 μM in 24, 48 and 72 h of treatment respectively. Apoptosis induction was also significantly higher in the hormonal-independent breast cancer cells, with 80.4% of dead cells in MDA-MB-231 and only 16.8% of dead in MCF-7 cells. As a result, G0/G1 cycle arrest was observed in MCF-7 cells and no cell cycle arrest at all was observed in MDA-MB-231 cells. Molecular docking showed a high affinity of QTCA-1 to PARP-1, Scr and PI3K/mTOR targets. These results suggest a strong activity of the 7-chloroquinoline derivative QTCA-1 in independent-hormonal cells and suggest selectivity for triple negative cells.

Alzheimer’s disease (AD) is a multifactorial pathology characterized by amyloid deposits, neurofibrillary formation, oxidative stress and cholinergic system dysfunction. In this sense, here we report the rational design of a multi-target directed ligand (MTDL) for AD based on virtual screening and bioinformatic analyses, exploring the molecular targets β-secretase (BACE-1), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE). After this screening, the compound with higher molecular docking affinity was selected, the 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide(QTC-4-MeOBnE). To further our studies, the protective effect of QTC-4-MeOBnE (0.1 and 1 mg/kg for 20 days) on STZ-induced sporadic AD mice was determined. QTC-4-MeOBnE pretreatment attenuated cognitive and memory deficit induced by STZ in an object recognition test, Y-maze, social recognition test and step-down passive avoidance. The mechanisms underlying this action might be attributed to the reduction of lipid peroxidation and reactive species formation in the prefrontal cortex and hippocampus of mice submitted to STZ. In addition, QTC-4-MeOBnE pretreatment abolished the up-regulation of AChE activity and the overexpression of GSK 3β and genes involved in amyloid cascade such as BACE-1, protein precursor amyloid, у-secretase, induced by STZ. Moreover, toxicological parameters were not modified by QTC-4-MeOBnE chronic treatment. This evidence suggests that QTC-4-MeOBnE exerts its therapeutic effect through multiple pathways involved in AD.

We describe herein our results on the synthesis of 4,7-bis((arylselanyl)ethynyl)benzo[c][1,2,5]thiadiazoles 3 by the silver-catalyzed direct selanylation of 4,7-diethynylbenzo[c][1,2,5]thiadiazole 1 with diaryl diselenides. Three new compounds were obtained in good yields using 10 mol% of AgNO3 as a catalyst under mild reaction conditions. In addition, the preliminary investigation of photophysical properties of the alkynyl derivatives by UV–Vis and steady-state emission fluorescence and electrochemical behavior was also presented. The photophysical properties of the new compounds were determined and experimental and theoretical DNA/HSA binding properties were assessed.

(Octylseleno)-xylofuranoside (OSX) is an organoselenium compound from the class of alkylseleno carbohydrates possessing a C8 alkyl chain. Members of this class of organoselenium compounds have promising pharmacological activities, among them are antioxidant and acute antidepressant-like activities with the involvement of monoaminergic system, as previously presented by our research group. The objective of the study was to investigate the possible involvement of cellular signalling pathways in the antidepressant-like effect caused by OSX (0.01 mg/kg, oral route (p.o.) by gavage) in the tail suspension test (TST) in mice. Mice were treated by intracerebroventricular (i.c.v.) injection either with vehicle or with H-89 (1 μg/site i.c.v., an inhibitor of protein kinase A-PKA), KN-62 (1 μg/site i.c.v., an inhibitor of Ca2+/calmodulin-dependent protein kinase II-CAMKII), chelerythrine (1 μg/site i.c.v., an inhibitor of protein kinase C-PKC) or PD098059 (5 μg/site i.c.v., an inhibitor of extracellular-regulated protein kinase 1/2-ERK1/2). Fifteen minutes after, vehicle or OSX was injected, and 30 min later, the TST and open field tests (OFT) were carried out. The antidepressant-like effect of orally administered OSX was blocked by treatment of the mice with H-89, KN-62, chelerythrine and PD098059; all inhibitors of signalling proteins involved with neurotrophic signalling pathways. The number of crossings in the OFT was not altered by treatment with OSX and/or signalling antagonists. The results demonstrated that OSX showed an antidepressant-like effect in the TST in mice through the activation of protein kinases PKA, PKC, CAMKII and ERK1/2 that are involved in intracellular signalling pathways.

We describe herein our results on the synthesis, antioxidant properties and chemical diversification of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles. These compounds were synthesized in high yields by the reaction of azidophenyl phenylselenides with a range of α-keto nitriles, using DMSO as the solvent in the presence of a catalytic amount of Et2NH (1 mol%). The synthesized compounds were screened for their in vitro antioxidant activity and 5-phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3a) exhibited the highest antioxidant effect. In addition, the obtained triazoyl carbonitriles were readily transformed into more complex products via a cycloaddition protocol with NaN3, affording bifunctional hybrids containing triazole and tetrazole systems in good to excellent yields.

Chronic pain and depressive disorders have been estimated to co-occur in up to 80% of patients and traditional antidepressants and analgesics have shown limited clinical efficacy. α- (phenylselanyl) acetophenone (PSAP) is an organic selenium compound which has already demonstrated antioxidant, antidepressant and antinociceptive activities in animal models, without showing acute toxicity. In view of develop more effective treatments to comorbid pain and depression, the purpose of this study was to evaluate the behavioral and biochemical effects of PSAP on reserpine induced pain-depression dyad model in mice as well to analyze the interaction of PSAP with specific targets by molecular docking analysis. Reserpine (0.5 mg/kg daily, for 3 days, i.p.) decreased the latency for the first episode of immobility and the swimming time, as well as increased the immobility time of mice in the modified forced swimming test (mFST). Reserpine also led to a significant decrease in nociceptive threshold in thermal hyperalgesia in the hot plate test. PSAP or imipramine (10 mg/kg daily, for 2 days, i.g.) reversed these alterations in both mFST and hot plate test. Additionaly, PSAP reduced nitrite and malondialdehyde (MDA) levels and catalase (CAT) activity in the cerebral cortex and hippocampus of reserpinised mice. PSAP also normalized monoamine oxidase (MAO-A and MAO-T) activity increased in reserpinised mice. According to the molecular docking analysis, PSAP has affinity to MAO-A, suggesting an inhibition of this enzyme. The data presented here show that PSAP had reversed effects in the pain-depression dyad induced by reserpine, possibly by its antioxidant property and MAO-A inhibition.

Organoselenium compounds and indoles have gained attention due to their wide range of pharmacological properties. Depression is a recurrent and disabling psychiatric illness and current evidences support that oxidative stress and neuroinflammation are mechanisms underlying the pathophysiology of this psychiatric condition. Here, we evaluated the effect of 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) in lipopolysaccharide (LPS)-induced depressive-like behaviour, neuroinflammation and oxidative stress in male mice. CMI pre-treatment (20 and 50 mg/kg, intragastrically) significantly attenuated LPS (0.83 mg/kg, intraperitoneally)-induced depressive-like behaviour in mice by reducing the immobility time in the tail suspension test (TST) and forced swimming test (FST). CMI pre-treatment ameliorated LPS-induced neuroinflammation by reducing the levels of interleukin (IL)-1β, IL-4 and IL-6 in the hippocampus and prefrontal cortex, as well as markers of oxidative damage. Additionally, we investigated the toxicological effects of CMI (200 mg/kg, i.g.) in the liver, kidney and brain through determination of the activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), δ-aminolevulinate dehydratase (δ-ALA-D) and creatinine levels. These biomarkers were not modified, indicating the possible absence of neuro-, hepato- and nephrotoxic effects. Our results suggest that CMI could be a therapeutic approach for the treatment of depression and other neuropsychiatric disorders associated with inflammation and oxidative stress.

A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

We describe herein our results on the synthesis, antioxidant properties and chemical diversification of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles. These compounds were synthesized in high yields by the reaction of azidophenyl phenylselenides with a range of α-keto nitriles, using DMSO as the solvent in the presence of a catalytic amount of Et2NH (1 mol%). The synthesized compounds were screened for their in vitro antioxidant activity and 5-phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3a) exhibited the highest antioxidant effect. In addition, the obtained triazoyl carbonitriles were readily transformed into more complex products via a cycloaddition protocol with NaN3, affording bifunctional hybrids containing triazole and tetrazole systems in good to excellent yields.