Selenylated Analogs of Tacrine: Synthesis, in Silico and in Vitro Studies of Toxicology and Antioxidant Properties.

We present our results on the synthesis and preliminary in silico and in vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2-aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20% to 87%. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated.

Development and In Vivo Assessment of 4-Phenyltellanyl-7-chloroquinoline-loaded Polymeric Nanocapsules in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common form of dementia in older people, and available treatments are palliative and produce undesirable side effects. The 4-phenyltellanyl-7-chloroquinoline (TQ) is an organochalcogen compound studied due to its pharmacological properties, particularly its antioxidant potential. However, TQ possesses some drawbacks such as low aqueous solubility and high toxicity, thus warranting the search for tools that improve the safety and effectiveness of new compounds. Here, we developed and investigated the biological effects of TQ-loaded polymeric nanocapsules (NCTQ) in an AD model in transgenic Caenorhabditis elegans expressing human Aß1-42 in their body-wall muscles and Swiss mice injected with Aß25-35. The NCTQ displayed good physicochemical properties, including nanometer size and maximum encapsulation capacity. The treatment showed low toxicity, reduced Aß peptide-induced paralysis, and activated an endoplasmic reticulum chaperone in the C. elegans model. The Aß injection in mice caused memory impairment, which NCTQ mitigated by improving working, long-term, and aversive memory. Additionally, no changes in biochemical markers were evidenced in mice, demonstrating that there was no hepatotoxicity in the tested doses. Altogether, these findings provide insights into the neuroprotective effects of TQ and indicate that NCTQ is a promising candidate for AD treatment.

QTC-4-MeOBnE Ameliorated Depressive-Like Behavior and Memory Impairment in 3xTg Mice.

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 ß-secretase (BACE), glycogen synthase kinase 3ß (GSK3ß), 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 (Aß) 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.

1-(7-Chloroquinolin-4-yl)-N-(4-Methoxybenzyl)-5-Methyl-1H-1,2, 3-Triazole-4- carboxamide Reduces Aß Formation and Tau Phosphorylation in Cellular Models of Alzheimer's Disease.

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 ß-secretase (BACE), Glycogen Synthase Kinase 3ß (GSK3ß) 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 (Aß) 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 GSK3ß 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.

Palladium-Catalyzed Carbonylative Synthesis of Aryl Selenoesters Using Formic Acid as an Ex Situ CO Source.

A new catalytic protocol for the synthesis of selenoesters from aryl iodides and diaryl diselenides has been developed, where formic acid was employed as an efficient, low-cost, and safe substitute for toxic and gaseous CO. This protocol presents a high functional group tolerance, providing access to a large family of selenoesters in high yields (up to 97%) while operating under mild reaction conditions, and avoids the use of selenol which is difficult to manipulate, easily oxidizes, and has a bad odor. Additionally, this method can be efficiently extended to the synthesis of thioesters with moderate-to-excellent yields, by employing for the first time diorganyl disulfides as precursors.

Synthesis and Evaluation of Antioxidant, Anti-Edematogenic and Antinociceptive Properties of Selenium-Sulfa Compounds.

Herein we describe results for the synthesis and synthetic application of 4-amino-3-(arylselenyl)benzenesulfonamides, and preliminary evaluation of antioxidant, anti-edematogenic and antinociceptive properties. This class of compounds was synthesized in good yields by a reaction of commercially available sulfanilamide and diorganyl diselenides in the presence of 10 mol% of I2 . Furthermore, the synthesized compound 4-amino-3-(phenylselenyl)benzenesulfonamide (3 a) was evaluated on complete Freund's adjuvant (CFA)-induced acute inflammatory pain. Dose- and time-response curves of antinociceptive effect of compound 3 a were performed using this experimental model. Also, the effect of compound 3 a was monitored in a hot-plate test to evaluate the acute non-inflammatory antinociception. The open-field test was performed to evaluate the locomotor and exploratory behaviors of mice. Oxidative stress markers, such as glutathione peroxidase activity; reactive species, non-protein thiols, and lipid peroxidation levels were performed to investigate the antioxidant action of compound 3 a. Our findings suggest that the antioxidant effect of compound 3 a may contribute to reducing the nociception and suppress the signaling pathways of inflammation on the local injury induced by CFA. Thus, compound 3 a reduced the paw edema as well as the hyperalgesic behavior in mice, being a promising therapeutic agent for the treatment of painful conditions.

Beneficial effects of QTC-4-MeOBnE in an LPS-induced mouse model of depression and cognitive impairments: The role of blood-brain barrier permeability, NF-κB signaling, and microglial activation.

Clinical and preclinical investigations have suggested a possible biological link betweenmajor 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 ß-secretase, glycogen synthase kinase 3ß, 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.

Transition-Metal-Free C-S, C-Se, and C-Te Bond Formation from Organoboron Compounds.

The present review describes the successful application of organoboron compounds in transition-metal-free C-S, C-Se, and C-Te bond formations. We presented studies regarding these C-Chalcogen bond formations using organoboron reagents, such as boronic acids, boronic esters, borate anions, and several sources of chalcogen atoms/moieties. Moreover, a broad range of transition-metal-free approaches to synthesize sulfides, selenides, and tellurides were described using conventional heating methods, which are sometimes green since they use green solvents, safe reagents, among others. Furthermore, protocols using alternative energy sources, including ultrasound, microwave irradiation, photocatalysis, and electrolytic processes, were also shown to be suitable. These protocols were applied to prepare a broad scope of functionalized chalcogenides with high molecular diversity. These studies and their proposed mechanisms were also reported herein in addition to the reuse of reaction promoters.

Effect of QTC-4-MeOBnE Treatment on Memory, Neurodegeneration, and Neurogenesis in a Streptozotocin-Induced Mouse Model of Alzheimer'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/ß-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.

7-chloro-4-(phenylselanyl) quinoline co-treatment prevent oxidative stress in diabetic-like phenotype induced by hyperglycidic diet in Drosophila melanogaster.

The goals of this work were to evaluate the effects produced by a hyperglycidic diet (HD) on Drosophila melanogaster and to verify the protective effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on this model. Adult flies were divided into eight groups of 50 flies each: (1) RD, (regular diet) (2) RD + 4-PSQ (25 µM), (3) HD 5%, (4) HD 10%, (5) HD 30% (6) HD 5% + 4-PSQ (25 µM), (7) HD 10% + 4-PSQ (25 µM) and (8) HD 30% + 4-PSQ (25 µM). Flies were exposed to a diet containing sucrose and or 4-PSQ for ten days, according to each group. At the end of treatment survival rate, longevity, hatch rate, food intake, glucose and triglyceride levels, as well as, some markers of oxidative stress, such as thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase (CAT) activities, protein thiol (PSH) and non-protein levels (NPSH) and cell viability assays (Resazurin and MTT) were evaluated. It was observed that HD's consumption was associated with lower survival of the flies, lower longevity, and increased levels of glucose, triglycerides, TBARS and increased SOD activities and CAT activities. Treatment with 25 µM 4-PSQ increased the satiety of flies, increased survival, reduced glucose, triglyceride and TBARS levels, increased hatching, and normalized SOD and CAT activities. These results suggest that 25 µM 4-PSQ had a potential antioxidant effect and provided greater satiety by attenuating the effects of high HD consumption on this model.

QTC-4-MeOBnE Rescues Scopolamine-Induced Memory Deficits in Mice by Targeting Oxidative Stress, Neuronal Plasticity, and Apoptosis.

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-3ß 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.

Organoselenotriazoles attenuate oxidative damage induced by mitochondrial dysfunction in mev-1 Caenorhabditis elegans mutants.

Organic selenium compounds have several pharmacological activities already described, as anti-inflammatory and antitumor activities, which have been attributed to their antioxidant effects. Because they are promising in pharmacology, the synthesis of these compounds has increased significantly. As many new molecules are synthesized the use of a simple model like Caenorhabditis elegans is highly advantageous for initial evaluation of the toxicity and therapeutic potential of these molecules. The objective of this study was to evaluate the toxicity and antioxidant capacity of a series of selenotriazoles compounds in C. elegans. The animals were exposed to the compounds in liquid medium for only 30 min at the first larval stage (L1). The compounds had no toxic effects at the concentrations tested. Treatment with selenotriazoles (10 µM) partially reversed the stress induced by the pesticide paraquat (1 mM). Se-Tz Ia compound partially increased the survival of worms treated with H2O2 (0.5 mM). The compounds also increased the longevity of mev-1 mutants, which have a reduced life span by the production of excessive reactive oxygen species (ROS) in the mitochondria caused by a mutation in complex II of the electron transport chain. In addition, the compounds reduced the levels of ROS determined by the fluorescent probe DCF-DA as well as also reduced catalase enzyme activity in these animals. Based on the results found, it is possible to conclude that the compounds have antioxidant activity mainly in oxidative stress condition generated by a mitochondrial dysfunction in C. elegans.

7-chloro-4-(phenylselanyl) quinoline prevents dopamine depletion in a Drosophila melanogaster model of Parkinson's-like disease.

Neurodegeneration in Parkinson's disease appears to be caused by multiple factors, including oxidative damage and an increase in acetylcholinesterase expression that can culminate in loss of dopaminergic neurons. A selenium-containing quinoline derivative, 7-chloro-4-(phenylselanyl) quinoline (4-PSQ), shows important pharmacological actions mainly attributed to its antioxidant and anticholinesterase properties. Thus, this study investigated the neuroprotective effect of 4-PSQ in a model of Parkinson's-like disease induced by rotenone (ROT) in Drosophila melanogaster and verified whether these effects are related to selenium levels. Adult flies were divided into: [1] control, [2] 4-PSQ (25 µM), [3] ROT (500 µM), and [4] 4-PSQ (25 µM) + ROT (500 µM) groups and exposed to a diet containing ROT and/or 4-PSQ for 7 days, according to their respective groups. Survival, behavioral, and ex vivo analyses were performed. Dopamine levels, reactive species levels (RS), lipid peroxidation (LPO), superoxide dismutase (SOD) and catalase (CAT) activity, and proteic thiol (PSH) and non-proteic thiol (NPSH) content in the head region were analyzed, while acetylcholinesterase (AChE) activity and selenium levels in the head and body regions were analyzed. 4-PSQ was able to reverse the ROT-induced deficits in flies, reestablish dopamine and selenium levels, reverse cholinergic deficits, improve motor function, and ameliorate mortality. Furthermore, 4-PSQ also reduced RS levels and LPO, and restored the activities of the antioxidant enzymes, SOD and CAT. Interestingly, a positive relationship between dopamine and selenium levels could be seen. Our results demonstrate the neuroprotective effect of 4-PSQ, and we suggest that the compound may act via different mechanisms, such as improving antioxidant defenses and consequently reducing oxidative damages, as well as having an anticholinesterase action, which together can prevent dopamine depletion, as these actions were correlated with the presence of selenium in the 4-PSQ molecule.

Correction: Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

[This corrects the article DOI: 10.1371/journal.pone.0187445.].

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

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.

7-Chloro-4-phenylsulfonyl quinoline, a new antinociceptive and anti-inflammatory molecule: Structural improvement of a quinoline derivate with pharmacological activity.

The present study was designed to examine the antinociceptive and anti-inflammatory effects of 7-chloro-4-phenylsulfonyl quinoline (PSOQ). Mice were orally (p.o) pretreated with PSOQ (0.01-10 mg/kg), meloxicam (10 mg/kg), 30 min prior to the acetic acid, hot-plate and open field tests. PSOQ reduced abdominal writhing induced by acetic acid, while meloxicam presented no effect. The latency time in the hot-plate test and locomotor/exploratory activities in the open field test were not altered by treatments. In order to evaluate the gastric tolerability after oral administration of PSOQ or meloxicam (10 mg/kg), mice were fasted for 18 h prior to drug exposure. Four hours later, the development of lesions was assessed. PSOQ and meloxicam did not induce ulcer at the dose and time evaluated. Indeed, anti-inflammatory and anti-edematogenic properties of PSOQ were investigated. For this, animals were pretreated with PSOQ (0.01-50 mg/kg; p.o.), meloxicam (50 mg/kg; p.o.), 30 min prior to croton oil application. PSOQ and meloxicam (50 mg/kg) diminished the edema formation and myeloperoxidase activity induced by croton oil in the ear tissue. Taken together these data demonstrated that PSOQ exerts acute anti-inflammatory and antinociceptive actions, suggesting that it may represent an alternative in the development of future new therapeutic strategies.