Bioactivity of selenium-containing pyridinium salts: Prospecting future pharmaceutical constituents to treat liver diseases involving oxidative stress.

Redox imbalance leads to oxidative stress that causes irreversible cellular damage. The incorporation of the antioxidant element selenium (Se) in the structure of pyridinium salts has been used as a strategy in chemical synthesis and can be useful in drug development. We investigated the antioxidant activity of Se-containing pyridinium salts (named Compounds 3A, 3B, and 3C) through in vitro tests. We focused our study on liver protein carbonylation, liver lipoperoxidation, free radical scavenging activity (1,1-diphenyl-2-picryl-hydrazil [DPPH]; 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid [ABTS]), and enzyme-mimetic activity assays (glutathione S-transferase [GST]-like; superoxide dismutase [SOD]-like). In addition, 2-(4-chlorophenyl)-2-oxoethyl)-2-((phenylselanyl)methyl)pyridin-1-ium bromide (3C) was selected to evaluate the acute oral toxicity in mice due to the best antioxidant profile. The three compounds were effective in reducing the levels of protein carbonylation and lipoperoxidation in the liver in a µM concentration range. All compounds demonstrated scavenger activity of DPPH and ABTS radicals, and GST-like action. No significant effects were detected in the SOD-like assay. Experimental data also showed that the acute oral treatment of mice with Compound 3C (50 and 300 mg/kg) did not cause mortality or change markers of liver and kidney functions. In summary, our findings reveal the antioxidant potential of Se-containing pyridinium salts in liver tissue, which could be related to their radical scavenging ability and mimetic action on the GST enzyme. They also demonstrate a low toxicity potential for Compound 3C. Together, the promising results open space for future studies on the therapeutic application of these molecules.

Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules.

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

Green Approach for the Synthesis of Chalcogenyl- 2,3-dihydrobenzofuran Derivatives Through Allyl-phenols/ Naphthols and Their Potential as MAO-B Inhibitors.

This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2 /DMSO catalytic system. All compounds were fully structurally characterized using 1 H and 13 C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.

Neuropharmacology of Organoselenium Compounds in Mental Disorders and Degenerative Diseases.

Neurodegenerative and mental disorders are a public health burden with pharmacological treatments of limited efficacy. Organoselenium compounds are receiving great attention in medicinal chemistry mainly because of their antioxidant and immunomodulatory activities, with a multi-target profile that can favor the treatment of multifactorial diseases. Therefore, the purpose of this review is to discuss recent preclinical studies about organoselenium compounds as therapeutic agents for the management of mental (e.g., depression, anxiety, bipolar disorder, and schizophrenia) and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis). We have summarized around 70 peer-reviewed articles from 2016 to the present that used in silico, in vitro, and/or in vivo approaches to assess the neuropharmacology of selenium- containing compounds. Among the diversity of organoselenium molecules investigated in the last five years, diaryl diselenides, Ebselen-derivatives, and Se-containing heterocycles are the most representative. Ultimately, this review is expected to provide disease-oriented information regarding the neuropharmacology of organoselenium compounds that can be useful for the design, synthesis, and pharmacological characterization of novel bioactive molecules that can potentially be clinically viable candidates.

Flower essential oil of Tagetes minuta mitigates oxidative stress and restores BDNF-Akt/ERK2 signaling attenuating inflammation- and stress-induced depressive-like behavior in mice.

Essential oils (EO) are plant extracts widely used for various pharmacological applications and their antioxidant and anti-inflammatory effects have received a lot of attention because they hold the potential to reduce oxidative stress, and neuroinflammation, alterations involved in the pathophysiology of major depressive disorder. This study examined the benefits of administration of flower EO of the Tagetes minuta (10 and 50 mg/kg, intragastric route) in attenuating behavioral, neurochemical, and neuroendocrine changes in animal models of depressive-like behavior induced by acute restraint stress and lipopolysaccharide (0.83 mg/kg, intraperitoneally). We demonstrated that the treatment of mice with flower EO of the T. minuta reversed the depressive-like behavior induced by stress or inflammatory challenge in mice. This effect is most likely due to the reversal of oxidative stress in the hippocampus of mice, the decrease in plasma corticosterone levels, and restoration of the mRNA levels of brain-derived neurotrophic factor, phosphatidylinositol-3-kinase, protein kinase B, and extracellular signal-regulated kinase 2. As an outcome, flower EO of the T. minuta has promising antidepressant properties and could be considered for new therapeutic strategies for major depressive disorder.

Synthesis and Antioxidant Activity of New Selenium-Containing Quinolines.

BACKGROUND: Quinoline derivatives have been attracted much attention in drug discovery, and synthetic derivatives of these scaffolds present a range of pharmacological activities. Therefore, organoselenium compounds are valuable scaffolds in organic synthesis because of their pharmacological activities and their use as versatile building blocks for regio-, chemo-and stereoselective reactions. Thus, the synthesis of selenium-containing quinolines has great significance, and their applicability range from simple antioxidant agents, to selective DNA-binding and photocleaving agents. OBJECTIVE: In the present study, we describe the synthesis and antioxidant activity in vitro of new 7- chloro-N(arylselanyl)quinolin-4-amines 5 by the reaction of 4,7-dichloroquinoline 4 with (arylselanyl)- amines 3. METHODS: For the synthesis of 7-chloro-N(arylselanyl)quinolin-4-amines 5, we performed the reaction of (arylselanyl)-amines 3 with 4,7-dichloroquinoline 4 in the presence of Et3N at 120 °C in a sealed tube. The antioxidant activities of the compounds 5 were evaluated by the following in vitro assays: 2,2- diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric ion reducing antioxidant power (FRAP), nitric oxide (NO) scavenging and superoxide dismutase-like activity (SOD-Like). RESULTS: 7-Chloro-N(arylselanyl)quinolin-4-amines 5a-d have been synthesized in yields ranging from 68% to 82% by the reaction of 4,7-dichloroquinoline 4 with arylselanyl-amines 3a-d using Et3N as a base, at 120 °C, in a sealed tube for 24 hours and tolerates different substituents, such as -OMe and -Cl, in the arylselanyl moiety. The obtained compounds 5a-d presented significant results concerning the antioxidant potential, which had an effect in the tests of inhibition of radical's DPPH, ABTS+ and NO, as well as in the analysis that evaluates the capacity (FRAP) and in the superoxide dismutase-like activity assay (SOD-Like). It is worth mentioning that 7-chloro- N(arylselanyl)quinolin-4-amine 5b presented excellent results, demonstrating a better antioxidant capacity when compared to the others. CONCLUSION: According to the obtained results, 7-chloro-N(arylselanyl)quinolin-4-amines 5 were synthesized in good yields by the reaction of 4,7-dichloroquinoline with arylselanyl-amines and tolerated different substituents in the arylselanyl moiety. The tested compounds presented significant antioxidant potential in the tests of inhibition of DPPH, ABTS+, and NO radicals, as well as in the FRAP and superoxide dismutase-like activity assays (SOD-Like).

Regioselective Synthesis of 1-Sulfanyl- and 1-Selanylindolizines.

We describe herein a new approach to prepare unprecedented bioactive indolizine motifs decorated with organosulfur and organoselenium groups. A total of 12 1-sulfanylindolizines and 2 1-selanylindolizines were prepared in excellent yields by an intramolecular annulation of easily prepared chalcogen-containing pyridinium salts. The reaction is fast (1 h at 70 °C or 5 min under sonication) and transition-metal-free, using glycerol as a green solvent.

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole promotes recovery of neuropathic pain and depressive-like behavior induced by partial constriction of the sciatic nerve in mice.

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole (CMI) is an organoselenium compound that presents antioxidant activity, antinociceptive, anti-inflammatory and antidepressive-like effect in mice in previous studies conducted by our research group. In this study, we evaluate the anti-allodynic, anti-hyperalgesic and antidepressant-like effects of CMI on partial sciatic nerve ligation (PSNL) in male adult Swiss mice (25-35 g) as well as the involvement of oxidative stress in these effects. Mice underwent PSNL surgery and after 4 weeks they were treated with CMI (10 mg/kg, intragastric route [i.g.]) or vehicle. The treatment with CMI (10 mg/kg, i.g.) reversed the increased the percentage of response to Von-Frey Hair (VFH) stimulation, decreased the latency time to nociceptive response in the hot-plate test, increased immobility time in the forced swimming test (FST) and decreased groomings activity in the splash test, all induced by PSNL. Additionally, CMI also reversed increased the levels of reactive oxygen species (ROS) and lipid peroxidation in cortex and hippocampus and plasmatic levels of corticosterone in mice, induced by PSNL. Results demonstrate that CMI reversed behavioral and biochemical alterations in the dyad pain-depression induced by PSNL and possibly modulation of oxidative system.

Ebselen inhibits the activity of acetylcholinesterase globular isoform G4 in vitro and attenuates scopolamine-induced amnesia in mice.

There is a well-known relationship between the cholinergic system and learning, memory, and other common cognitive processes. The process for researching and developing new drugs has lead researchers to repurpose older ones. This study investigated the effects of ebselen on the activity of acethylcholinesterase (AChE) isoforms in vitro and in an amnesia model induced by scopolamine in Swiss mice. In vitro, ebselen at concentrations equal or higher than 10 µM inhibited the activity of cortical and hippocampal G4/AChE, but not G1/AChE isoform. Treatment of mice with ebselen (50 mg/kg, i.p.) was effective against impairment of spatial recognition memory in both Y-maze and novel object recognition tests induced by scopolamine (1 mg/kg, i.p.). Ebselen (50 mg/kg) inhibited hippocampal AChE activity in mice. The present study demonstrates that ebselen inhibited the G4/AChE isoform in vitro and elicited an anti-amnesic effect in a mouse model induced by scopolamine. These findings reveal ebselen as a potential compound in terms of opening up valid therapeutic avenues for the treatment of memory impairment diseases.

A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice.

Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression.

2-Phenylethynyl-butyltellurium enhances learning and memory impaired by scopolamine in mice.

Taking into account the memory-enhancing properties of 2-phenylethynyl-butyltellurium (PEBT) and the constant search for drugs that improve cognitive performance, the present study was designed to investigate the effect of PEBT on cognitive impairment induced by scopolamine in mice. PEBT (10 mg/kg, gavage) was administered to mice 1 h before the probe trial in the Morris water maze task. Memory impairment was induced by scopolamine (1 mg/kg, intraperitoneally) 30 min before the probe trial. PEBT significantly ameliorated the scopolamine-induced impairment of long-term memory, as indicated by a decrease in escape latency and an increase in the number of crossings of the platform location when compared with the amnesic mice. To evaluate the effect of PEBT on different phases of memory (acquisition, consolidation, and retrieval) impaired by scopolamine, the step-down inhibitory avoidance task was used. Scopolamine was administered 30 min before training (acquisition), test (retrieval), or immediately after training (consolidation). PEBT, administered 30 min before scopolamine, increased step-down latency in memory-impaired mice, improving the consolidation and retrieval stages, but not acquisition. No significant alterations in locomotor or exploratory behaviors were found in animals treated with PEBT and/or scopolamine. PEBT improved memory deficits during consolidation and retrieval induced by scopolamine.

Therapeutic effect of organoselenium dietary supplementation in a sporadic dementia of Alzheimer's type model in rats.

It is known that selenium (Se) might play different roles in the progression of Alzheimer's disease (AD), but there is a lack of evidence that proves whether supplementation with Se is beneficial or not for the treatment of AD. Thus, the aim of the current study was to investigate the therapeutic effect of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)], an organoselenium compound, against streptozotocin (STZ)-induced sporadic dementia of Alzheimer's type (SDAT) in rats. Male Wistar rats received STZ twice daily (1.0 mg/8 µl; 4 µl/ventricle) for 21 days. After 21 days of STZ injection, regular-diet-fed rats were supplemented with 10 ppm of (MeOPhSe)(2) during 30 days. At the end of this period, the rats were challenged in the Morris water maze and step-down passive avoidance tasks. The activity of acetylcholinesterase (AChE), deficit in cerebral energy metabolism (measurement of adenosine 5-triphosphate and adenosine 5-diphosphate levels), and oxidative and nitrosative stress were determined in the cortex and hippocampus of rats. The results demonstrated that (MeOPhSe)(2) dietary supplementation reverted STZ-induced memory impairment of rats in both cognitive tasks. The findings also indicated that (MeOPhSe)(2) dietary supplementation reverted oxidative stress in the STZ group (decreased reactive species and tyrosine nitration levels and enhanced nonprotein thiol levels). Moreover, (MeOPhSe)(2) dietary supplementation normalized AChE activity, which was enhanced by STZ injection, but did not revert the deficit in cerebral energy metabolism caused by STZ. The results of the present study indicated the therapeutic effect of the (MeOPhSe)(2)-supplemented diet in a rat model of SDAT.

Protective effect of diphenyl diselenide on ischemia and reperfusion-induced cerebral injury: involvement of oxidative stress and pro-inflammatory cytokines.

Cerebrovascular diseases, including ischemic stroke, are associated with high mortality worldwide. Oxidative stress and inflammation are important pathophysiological mechanisms involved in post-ischemic cerebral injury. The present study was designed to investigate the potential protective effect of diphenyl diselenide (PhSe)(2), an organoselenium compound with antioxidant and anti-inflammatory properties, against ischemia/reperfusion (I/R) insult in rat brain. The experimental model adopted was that of surgically-induced brain ischemia, performed by means of bilateral common carotid artery occlusion in rats. The effect of a single oral dose of (PhSe)(2) (50 mg/kg), administered 30 min before the onset of ischemia, was investigated by assessing cerebral oxidative stress-related biochemical parameters and pro-inflammatory cytokines in plasma of rats. The results demonstrated an increase in the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and nitrate/nitrite as well as the alteration in the non-enzymatic and enzymatic (catalase and superoxide dismutase) antioxidant defense system induced by I/R insult in rat brain. I/R insult increased the levels of IL-1ß, IL-6, TNF-α and INF-γ in plasma of rats. The administration of (PhSe)(2) restored cerebral levels of MDA, ROS, nitrate/nitrite and antioxidant defenses of rats exposed to I/R insult. (PhSe)(2) markedly reduced pro-inflammatory cytokines in plasma of I/R rats. I/R insult increased the plasma levels of tissue damage markers, such as creatine kinase and α-1-acid glycoprotein. Pretreatment with (PhSe)(2) was effective in reducing the levels of these proteins. In addition, (PhSe)(2) attenuated cerebral histological alterations induced by I/R. This study showed for the first time the in vivo protective effect of (PhSe)(2) against oxidative stress and pro-inflammatory cytokines-induced by I/R insult in rats.

m-Trifluoromethyl-diphenyl diselenide attenuates pentylenetetrazole-induced seizures in mice by inhibiting GABA uptake in cerebral cortex slices.

The present study investigated the anticonvulsive effect of the disubstituted diaryl diselenides diphenyl diselenide (PhSe)(2), m-trifluoromethyl-diphenyl diselenide (m-CF(3)-C(6)H(4)Se)(2), p-chloro-diphenyl diselenide (p-Cl-C(6)H(4)Se)(2) and p-methoxyl-diphenyl diselenide (p-CH(3)O-C(6)H(4)Se)(2) on a chemical model of seizure induced by pentylenetetrazole (PTZ) in mice. (PhSe)(2), (p-Cl-C(6)H(4)Se)(2) and (p-CH(3)O-C(6)H(4)Se)(2) did not abolish seizures induced by PTZ in mice. (m-CF(3)-C(6)H(4)Se)(2) at the dose of 100 mg/kg significantly prolonged the latency of the onset of the first convulsive episode and reduced the number of animals that presented seizures. To investigate the possible mechanisms involved in the anticonvulsant effect of (m-CF(3)-C(6)H(4)Se)(2), mice were submitted to different associations (all drugs in a sub-effective dose); aminooxyacetic acid hemihydrochloride (AOAA, a gamma-aminobutyric acid (GABA)-T inhibitor), diazepam (a GABA(A) receptor agonist) or DL-2,4-diamino-n-butyric acid hydrochloride (DABA, an inhibitor of GABA uptake) were pre-administered together with (m-CF(3)-C(6)H(4)Se)(2). (m-CF(3)-C(6)H(4)Se)(2) + DABA abolished seizures induced by PTZ in mice. (m-CF(3)-C(6)H(4)Se)(2) administered alone or with PTZ decreased the levels of GABA uptake in cerebral cortex slices. The present study demonstrates that (m-CF(3)-C(6)H(4)Se)(2) exerts anticonvulsant action by decreasing the levels of GABA uptake.