Iodine/Oxone® oxidative system for the synthesis of selenylindoles bearing a benzenesulfonamide moiety as carbonic anhydrase I, II, IX, and XII inhibitors.

A wide range of 3-selenylindoles were synthesized via an eco-friendly approach that uses Oxone® as the oxidant in the presence of a catalytic amount of iodine. This mild and economical protocol showed broad functional group tolerance and operational simplicity. A series of novel selenylindoles bearing a benzenesulfonamide moiety were also synthesized and evaluated as carbonic anhydrase inhibitors of the human (h) isoforms hCa I, II, IX, and XII, which are involved in pathologies such as glaucoma and cancer. Several derivatives showed excellent inhibitory activity towards these isoforms in the nanomolar range, lower than that shown by acetazolamide.

Selanylimidazopyridine abolishes inflammation- and stress-induced depressive-like behaviors by modulating the oxido-nitrosative system.

The 3-[(4-methoxyphenyl)selanyl]-2-phenylimidazo[1,2-a] pyridine (MPI), a novel organic selenium compound, has been receiving increased attention due to its antioxidant effects and its ability to protect against depression-like behaviours. However, it remains elusive whether MPI is able to reverse depressive-like symptoms and biochemical alterations in mice. In the present work, we explored the ability of MPI (10 mg/kg, i.g.) to reverse inflammation- and stress-induced depression-like behaviours in mice injected with tumour necrosis factor (TNF-α) or submitted to acute restraint stress. Depression-like behaviours were evaluated by the tail suspension and splash test and the open field test was used to evaluate the locomotor activity of mice. The prefrontal cortex and hippocampus of mice were used for the evaluation of parameters of oxidonitrosative stress. Here, we showed that a single administration of MPI abolished the depressive-like behaviours induced by TNF-α and acute restraint stress. The oxidative and nitrosative stress presented in mice with depression-like behaviours were also decreased by MPI in the prefrontal cortex and hippocampus. Our findings suggest that MPI presents antidepressant-like activity which is associated with the biochemical regulation of oxidative stress in prefrontal cortex and hippocampus of mice, arising as a promising strategy for the management of depressive symptoms.

Neuroprotective Effect of 3-[(4-Chlorophenyl)selanyl]-1-methyl-1H-indole on Hydrogen Peroxide-Induced Oxidative Stress in SH-SY5Y Cells.

Extensive data have reported the involvement of oxidative stress in the pathogenesis of neuropsychiatric disorders, prompting the pursuit of antioxidant molecules that could become adjuvant pharmacological agents for the management of oxidative stress-associated disorders. The 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has been reported as an antioxidant and immunomodulatory compound that improves depression-like behavior and cognitive impairment in mice. However, the exact effect of CMI on specific brain cells is yet to be studied. In this context, the present study aimed to evaluate the antioxidant activity of CMI in H2O2-induced oxidative stress on human dopaminergic neuroblastoma cells (SH-SY5Y) and to shed some light into its possible mechanism of action. Our results demonstrated that the treatment of SH-SY5Y cells with 4 µM CMI protected them against H2O2 (343 µM)-induced oxidative stress. Specifically, CMI prevented the increased number of reactive oxygen species (ROS)-positive cells induced by H2O2 exposure. Furthermore, CMI treatment increased the levels of reduced glutathione in SH-SY5Y cells. Molecular docking studies demonstrated that CMI might interact with enzymes involved in glutathione metabolism (i.e., glutathione peroxidase and glutathione reductase) and H2O2 scavenging (i.e., catalase). In silico pharmacokinetics analysis predicted that CMI might be well absorbed, metabolized, and excreted, and able to cross the blood-brain barrier. Also, CMI was not considered toxic overall. Taken together, our results suggest that CMI protects dopaminergic neurons from H2O2-induced stress by lowering ROS levels and boosting the glutathione system. These results will facilitate the clinical application of CMI to treat nervous system diseases associated with oxidative stress.

A Simple Zinc-Mediated Method for Selenium Addition to Michael Acceptors.

In this work, we focused our attention on seleno-Michael type reactions. These were performed using zinc-selenolates generated in situ from diphenyl diselenide 1, 1,2-bis(3-phenylpropyl)diselenide 30, and protected selenocystine 31 via an efficient biphasic Zn/HCl-based reducing system. Alkenes with a variety of electron-withdrawing groups were investigated in order to gauge the scope and limitations of the process. Results demonstrated that the addition to acyclic α,ß-unsaturated ketones, aldehydes, esters amides, and acids was effectively achieved and that alkyl substituents at the reactive ß-centre can be accommodated. Similarly, cyclic enones undergo efficient Se-addition and the corresponding adducts were isolated in moderate to good yield. Vinyl sulfones, α,ß-unsaturated nitriles, and chalcones are not compatible with these reaction conditions. A recycling experiment demonstrated that the unreacted Zn/HCl reducing system can be effectively reused for seven reaction cycles (91% conversion yield at the 7° recycling rounds).

Toxicological evaluation of 3-(4-Chlorophenylselanyl)-1-methyl-1H-indole through the bovine oocyte in vitro maturation model.

The development of new bioactive molecules based on the molecular hybridization has been widely explored. In line with this, reliable tests should be employed to give information about the toxicology of these new molecules. In this sense, the use of in vitro tests is a valuable tool, especially the in vitro maturation of oocytes (IVM), which is an efficient resource to discover the potential toxicity of synthetic molecules. Thus, the aim of the present study was to evaluate the toxicological effects of the selenium-containing indolyl compound 3-(4-Chlorophenylselanyl)-1-methyl-1H-indole (CMI), on different quality parameters of bovine oocytes through the IVM. Different concentrations of the CMI compound (0, 25, 50, 100, 200 µM) were supplemented during the in vitro maturation process. After, the oocyte maturation rate, glutathione (GSH) levels, reactive oxygen species (ROS) levels, membrane, and mitochondrial integrity were evaluated. The results showed that the lowest concentration of CMI induced the highest GSH production (P < 0.05), an important marker of cytoplasmic quality and maturation. All treatments increased ROS production in relation to non-supplementation (P < 0.05). In addition, oocyte maturation was reduced only with the highest concentration of CMI (P < 0.05). Supplementation with CMI did not impact mitochondrial activity, integrity and cell membrane. To our knowledge, this is the first study that evaluates CMI on the oocyte in vitro maturation process. Importantly, our results did not find any toxic effect of CMI on bovine oocytes. CMI was efficient for cytoplasmic maturation by promoting an increase in the intracellular levels of glutathione.

Depression-like behavior, hyperglycemia, oxidative stress, and neuroinflammation presented in diabetic mice are reversed by the administration of 1-methyl-3-(phenylselanyl)-1H-indole.

Oxidative stress and neuroinflammation are found both in diabetes mellitus and major depressive disorder (MDD). In addition to damage in peripheral organs, such as liver and kidney, diabetic patients have a higher risk of developing depression. In this sense, the objective of the present study was to characterize the antidepressant-like effect of a selenium-containing compound, the 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI), in streptozotocin (STZ)-induced diabetic mice. STZ (200 mg/kg, i.p.) was used to induce diabetes mellitus type I, and after seven days, the administration of MFSeI (10 mg/kg, i.g.) was initiated and followed for the next 14 days. Twenty-four hours after the last administration of MFSeI, the behavioral tests were performed, followed by euthanasia. The treatment with MFSeI was able to reverse the hyperglycemia induced by STZ. MFSeI also decreased the plasma levels of biomarkers of liver and kidney damage. Importantly, MFSeI reversed the depression-like behavior induced by STZ in the tail suspension test and forced swimming test without promoting locomotor alterations. Furthermore, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortex (PFC), hippocampus (HC), liver, and kidney of STZ-treated mice. Treatment with MFSeI also decreased the expression of tumor necrosis factor-alpha, inducible nitric oxide synthase and indoleamine 2,3-dioxygenase, while increasing the expression of interleukin-10, insulin receptor substrate-1 and glucose transport-4 in the PFC and HC of mice. Taken together, the results indicate the effectiveness of MFSeI against depression-like behavior and central and peripheral complications caused by diabetes in mice.

The antioxidant and immunomodulatory compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole attenuates depression-like behavior and cognitive impairment developed in a mouse model of breast tumor.

Psychiatric alterations are often found in patients with breast cancer even before the initiation of adjuvant therapy, resulting in a poor quality of life. It has become accepted that neuroinflammation and oxidative stress are involved in the pathophysiology of depression and cognitive impairment. Herein, we tested the hypothesis that treatment with the antioxidant and immunomodulatory selenium-containing compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI)could attenuate behavioral and neurochemical alterations in a mammary (4T1) tumor model. Female BALB/c mice were subcutaneously inoculated with 4T1 cancer cells (1 × 105 cells/mice) or PBS. From days 14 to 20, mice received daily gavage with canola oil or CMI. On day 21, mice were submitted to behavioral tests followed by euthanasia. We found that CMI did not alter tumor growth, body weight, and body temperature in tumor-bearing mice. Importantly, treatment with CMI abrogated tumor-induced depression-like behavior and cognitive impairment. By the time CMI improved the behavioral alterations, it had reduced tumor-induced neuroinflammation (altered expression of NFκB, IL-1ß, TNF-α, IL-10, IDO, and COX-2) and oxidative stress (altered expression of iNOS and Nrf2, and levels of reactive species, nitric oxide, lipid peroxidation, and superoxide dismutase activity) in the prefrontal cortices and hippocampi of mice. A molecular docking approach suggested the ability of CMI to inhibit the activity of iNOS and COX-2. Together, our results indicate that CMI treatment may attenuate depression and cognitive impairment in 4T1 tumor-bearing mice, and be a groundbreaking strategy for the treatment of cancer-related psychiatric symptoms to improve the quality of life of cancer patients.

The selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole reverses depressive-like behavior induced by acute restraint stress in mice: modulation of oxido-nitrosative stress and inflammatory pathway.

RATIONALE AND OBJECTIVES: Stress-induced alterations in oxidative and inflammatory parameters have been implicated in the pathophysiology of mood disorders. Based on the antioxidant and anti-inflammatory properties of the selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI), we assessed its ability to reverse depression-like behavioral alterations, neuroinflammation, and oxidative imbalance induced by acute restraint stress. METHODS: Mice submitted to restraint for 240 min received CMI (1 or 10 mg/kg, orally) 10 min after the end of the stress induction. Behavioral and biochemical tests were carried out after further 30 min. RESULTS: Restraint-induced depression-like behavior in the tail suspension test (TST), splash test, and new object exploration test was reversed by CMI. None of the treatments evoked locomotor alteration. In addition, CMI abrogated restraint-induced increases in plasma levels of corticosterone and in markers of oxidative stress and impaired superoxide dismutase and catalase activity in the prefrontal cortex (PFC) and hippocampus (HC). CMI also blocked stress-induced downregulation of mRNA levels of glucocorticoid receptor and brain-derived neurotrophic factor and upregulation of nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis alpha, indoelamine-2,3-dioxygenase, and glycogen synthase kinase 3 beta in PFC and HC. CONCLUSIONS: These preclinical results indicate that administration of selenium-containing compounds might help to treat depression associated with inflammation and oxidative stress. Graphical abstract ᅟ.

Antioxidant and antidepressant-like activities of semi-synthetic α-phenylseleno citronellal.

In this study, the antioxidant and antidepressant-like activities of the semi-synthetic compound α-phenylseleno citronellal (PhSeCIT) and the natural terpenoid R-citronellal (CIT) were evaluated. The biological potential of PhSeCIT and CIT was evaluated by antioxidant in vitro assays, such as 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), ferric ion reducing antioxidant power (FRAP) and linoleic acid oxidation. The compounds were also assessed by ex vivo tests to determine the acute toxicity, levels of thiobarbituric acid reactive species (TBARS), δ-aminolevulinate dehydratase (δ-Ala-D) and Na(+)/K(+) ATPase activities. The antidepressant-like activity of compounds in the tail suspension test (TST) and forced swimming test (FST) was also investigated. The results demonstrated that the addition of an organoselenium group to (R)-citronellal increased its antioxidant properties, since PhSeCIT showed better activity than CIT. The treatment of mice with both compounds did not cause death of any animals. The levels of TBARS were significantly reduced by PhSeCIT in liver and cortex of animals, whereas CIT did not alter these parameters. In the TST and FST, PhSeCIT showed promising antidepressant-like activity, while CIT was not active in this test. Taken together, these data demonstrate the role of selenium in the antioxidant and antidepressant-like activities of (R)-citronellal.

Involvement of serotoninergic and adrenergic systems on the antidepressant-like effect of E. uniflora L. leaves essential oil and further analysis of its antioxidant activity.

In this work we evaluated antidepressant-like effect of E. uniflora leaves EO employing the tail suspension test. The involvement of serotonergic and adrenergic systems was appraised. EO was administered by oral route (p.o.) in mice and the doses of 10 and 50mg/kg exhibited antidepressant-like action in the TST. The effect of EO (10mg/kg) was prevented by the pretreatment of mice with ketanserin (5mg/kg, intraperitoneal), prazosin (0.1mg/kg, i.p.) and yohimbine (0.1mg/kg, i.p.). In addition, further analysis of the in vitro antioxidant effect of the EO was made against lipid oxidation. The results revealed that EO has a potent antioxidant activity and therapeutic potential for the development of phytomedicines with antidepressant and antioxidant properties.

Essential oil of the leaves of Eugenia uniflora L.: antioxidant and antimicrobial properties.

Essential oil (EO) of the leaves of Eugenia uniflora L. (Brazilian cherry tree) was evaluated for its antioxidant, antibacterial and antifungal properties. The acute toxicity of the EO administered by oral route was also evaluated in mice. The EO exhibited antioxidant activity in the DPPH, ABTS and FRAP assays and reduced lipid peroxidation in the kidney of mice. The EO also showed antimicrobial activity against two important pathogenic bacteria, Staphylococcus aureus and Listeria monocytogenes, and against two fungi of the Candida species, C. lipolytica and C. guilliermondii. Acute administration of the EO by the oral route did not cause lethality or toxicological effects in mice. These findings suggest that the EO of the leaves of E. uniflora may have the potential for use in the pharmaceutical industry.