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.

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.

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.

In vitro and in silico trichomonacidal activity of 2,8-bis(trifluoromethyl) quinoline analogs against Trichomonas vaginalis.

Trichomoniasis is a great public health burden worldwide and the increase in treatment failures has led to a need for finding alternative molecules to treat this disease. In this study, we present in vitro and in silico analyses of two 2,8-bis(trifluoromethyl) quinolines (QDA-1 and QDA-2) against Trichomonas vaginalis. For in vitro trichomonacidal activity, up to seven different concentrations of these drugs were tested. Molecular docking, biochemical, and cytotoxicity analyses were performed to evaluate the selectivity profile. QDA-1 displayed a significant effect, completely reducing trophozoites viability at 160 µM, with an IC50 of 113.8 µM, while QDA-2 at the highest concentration reduced viability by 76.9%. QDA-1 completely inhibited T. vaginalis growth and increased reactive oxygen species production and lipid peroxidation after 24 h of treatment, but nitric oxide accumulation was not observed. In addition, molecular docking studies showed that QDA-1 has a favorable binding mode in the active site of the T. vaginalis enzymes purine nucleoside phosphorylase, lactate dehydrogenase, triosephosphate isomerase, and thioredoxin reductase. Moreover, QDA-1 presented a level of cytotoxicity by reducing 36.7% of Vero cells' viability at 200 µM with a CC50 of 247.4 µM and a modest selectivity index. In summary, the results revealed that QDA-1 had a significant anti-T. vaginalis activity. Although QDA-1 had detectable cytotoxicity, the concentration needed to eliminate T. vaginalis trophozoites is lower than the CC50 encouraging further studies of this compound as a trichomonacidal agent.

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.

Komagataella pastoris KM71H modulates neuroimmune and oxidative stress parameters in animal models of depression: A proposal for a new probiotic with antidepressant-like effect.

Many studies have suggested that imbalance of the gut microbial composition leads to an increase in pro-inflammatory cytokines and promotes oxidative stress, and this are directly associated with neuropsychiatric disorders, including major depressive disorder (MDD). Clinical data indicated that the probiotics have positive impacts on the central nervous system and thus may have a key role to treatment of MDD. This study examined the benefits of administration of Komagataella pastoris KM71H (8 log UFC·g-1/animal, intragastric route) in attenuating behavioral, neurochemical, and neuroendocrine changes in animal models of depressive-like behavior induced by repeated restraint stress and lipopolysaccharide (0.83 mg/kg). We demonstrated that pretreatment of mice with this yeast prevented depression-like behavior induced by stress and an inflammatory challenge in mice. We believe that this effect is due to modulation of the permeability of the blood-brain barrier, restoration in the mRNA levels of the Nuclear factor kappa B, Interleukin 1ß, Interferon γ, and Indoleamine 2 3-dioxygenase, and prevention of oxidative stress in the prefrontal cortices, hippocampi, and intestine of mice and of the decrease the plasma corticosterone levels. Thus, we conclude that K. pastoris KM71H has properties for a new proposal of probiotic with antidepressant-like effect, arising as a promising therapeutic strategy for MDD.

Bis-triazolylchalcogenium-Functionalized Benzothiadiazole Derivatives as Light-up Sensors for DNA and BSA.

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.

Effect of a purine derivative containing selenium to improve memory decline and anxiety through modulation of the cholinergic system and Na+/K+-ATPase in an Alzheimer's disease model.

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.

7-Chloroquinoline-1,2,3-triazoyl carboxamides induce cell cycle arrest and apoptosis in human bladder carcinoma cells.

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.

The combination of Brazilian red propolis and recombinant protein rCP01850 in the immunoprophylaxis of Corynebacterium pseudotuberculosis infection in mice.

The immunomodulatory properties of Brazilian red propolis (BRP) have been already described. Also, propolis have been proved to have antibacterial activity on Corynebacterium pseudotuberculosis. An adjuvant effect of red propolis oil was able to induce a significant anti-C. pseudotuberculosis humoral immune response. Here, we demonstrate for the first time the immunostimulant property of BRP hydroalcoholic extract (BRPHE) in a recombinant vaccine against caseous lymphadenitis. Mice BALB/c were allocated in three groups inoculated with: sterile saline solution (G1); BRPHE (G2); or BRPHE combined with the C. pseudotuberculosis rCP01850 recombinant protein (G3) in two doses within a 21-days-interval. Blood samples were collected for the total IgG, IgG1 and IgG2a measurement. Mice were challenged with a virulent C. pseudotuberculosis strain, and other 6 mice were used for IFN-γ and IL-10 levels determination after splenocyte stimulation with the recombinant antigen. G3 showed higher significant levels of antibodies on the 42nd experimental day, with a high IgG2a/IgG1 proportion. G2 and G3 presented significant production of IFN-γ and IL-10, while G3 presented the higher levels of IFN-γ (p < 0.05). After challenge, G2 showed a survival rate of 20%, while 70% of mice from G3 survived the experimental challenge. In conclusion, BRPHE used alone has immunostimulant properties specially on cellular immune response, and when used in combination with the recombinant protein rCP01850 induces cellular and humoral immune responses as well as a significant survival of inoculated 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.

Evaluation of the effect of synthetic compounds derived from azidothymidine on MDA-MB-231 type breast cancer cells.

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.

Evaluation of antioxidant activity and toxicity of sulfur- or selenium-containing 4-(arylchalcogenyl)-1H-pyrazoles.

Pyrazoles represent a significant class of heterocyclic compounds that exhibit pharmacological properties. The present study aimed to investigate the antioxidant potential of pyrazol derivative compounds in brain of mice in vitro and the effect of pyrazol derivative compounds in the oxidative damage and toxicity parameters in mouse brain and plasma of mice. The compounds tested were 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazol (1a), 3,5-dimethyl-4-(phenylselanyl)-1H-pyrazole (2a), 4-((4-methoxyphenyl)selanyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (3a), 4-((4-chlorophenyl)selanyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4a), 3,5-dimethyl-1-phenyl-4-(phenylthio)-1H-pyrazole (1b), 3,5-dimethyl-4-(phenylthio)-1H-pyrazole (2b), 4-((4-methoxyphenyl)thio)-3,5-dimethyl-1-phenyl-1H-pyrazole (3b), 4-((4-chlorophenyl)thio)-3,5-dimethyl-1-phenyl-1H-pyrazole (4b), and 3,5-dimethyl-1-phenyl-1H-pyrazole (1c). In vitro, 4-(arylcalcogenyl)-1H-pyrazoles, at low molecular range, reduced lipid peroxidation and reactive species in mouse brain homogenates. The compounds also presented ferric-reducing ability as well nitric oxide-scavenging activity. Especially compounds 1a, 1b, and 1c presented efficiency to 1,1-diphenyl-2-picryl-hydrazyl-scavenging activity. Compounds 1b and 1c presented 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)-scavenging activity. In vivo assays demonstrated that compounds 1a, 1b, and 1c (300 mg/kg, intragastric, a single administration) did not cause alteration in the of δ-aminolevulinic acid dehydratase activity, an enzyme that exhibits high sensibility to prooxidants situations, in the brain, liver, and kidney of mice. Compound 1c reduced per se the lipid peroxidation in liver and brain of mice. Toxicological assays demonstrate that compounds 1a, 1b, and 1c did not present toxicity in the aspartate aminotransferase, alanine aminotransferase, urea, and creatinine levels in the plasma. In conclusion, the results demonstrated the antioxidant action of pyrazol derivative compounds in in vitro assays. Furthermore, the results showed low toxicity of compounds in in vivo assays.

2'-Hydroxychalcones as an alternative treatment for trichomoniasis in association with metronidazole.

The treatment for trichomoniasis, based on 5'-nitroimidazol agents, has been presenting failures related to allergic reactions, side effects, and the emergence of resistant isolates. There are no alternative drugs approved for the treatment of these cases; thus, the search for new active molecules is necessary. In this scenario, chalcones have been extensively studied for their promising biological activities. Here, we presented the synthesis of three hydroxychalcones (3a, b, and c), in vitro and in silico analyses against Trichomonas vaginalis. The in vitro biological evaluation showed that hydroxychalcone 3c presented anti-T. vaginalis activity, with complete death in 12 h of incubation at minimum inhibitory concentration (MIC) of 100 µM. 3c showed a dose-dependent cytotoxicity against mammalian VERO cell line, but the association of 3c at 12.5 µM and metronidazole (MTZ) at 40 µM showed 95.31% activity against T. vaginalis trophozoites after 24 h of exposure and did not affect the VERO cell growth, appearing to be a good alternative. In silico analysis by molecular docking showed that 3c could inhibit the activity of TvMGL (methionine gamma-lyase), TvLDH (lactate dehydrogenase), and TvPNP (purine nucleoside phosphorylase) affecting the T. vaginalis survival and also suggesting a different mechanism of action from MTZ. Therefore, these results propose that hydroxychalcones are promising anti-T. vaginalis agents and must be considered for further investigations regarding trichomoniasis treatment.

Antioxidant compound (E)-2-benzylidene-4-phenyl-1,3-diselenole protects rats against thioacetamide-induced acute hepatotoxicity.

The aim of this study was to investigate whether (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) protects against hepatotoxicity induced by thioacetamide (TAA). On the first day of treatment, male adult Wistar rats received BPD (10 or 50 mg·kg-1). On the second day, the rats received a single intraperitoneal injection of TAA (400 mg·kg-1). Twenty-four hours after TAA administration, biochemical determinations and liver histological analysis were carried out. BPD (50 mg·kg-1) reduced plasma aspartate and alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities increased by TAA exposure. Treatment with BPD was effective against increased lipid peroxidation levels and attenuated a decrease in hepatic reduced glutathione and ascorbic acid levels as well as an inhibition of glutathione peroxidase activity caused by TAA exposure. The higher dose of BPD protected against the inhibition of hepatic δ-aminolevulinic dehydratase activity induced by TAA. Finally, histopathological examination of the liver showed that BPD markedly ameliorated TAA-induced hepatic injury. In conclusion, BPD protected against hepatotoxicity and oxidative stress caused by TAA exposure in rats.

Meloxicam-loaded nanocapsules as an alternative to improve memory decline in an Alzheimer's disease model in mice: involvement of Na(+), K(+)-ATPase.

The objective of this study was to investigate the effect of meloxicam-loaded nanocapsules (M-NC) on the treatment of the memory impairment induced by amyloid ß-peptide (aß) in mice. The involvement of Na(+), K(+)-ATPase and cyclooxygenase-2 (COX-2) activities in the hippocampus and cerebral cortex was also evaluated. Mice received aß (3 nmol/ 3 µl/ per site, intracerebroventricular) or vehicle (3 µl/ per site, i.c.v.). The next day, the animals were treated with blank nanocapsules (17 mL/kg) or M-NC (5 mg/kg) or free meloxicam (M-F) (5 mg/kg). Treatments were performed every other day, until the twelfth day. Animals were submitted to the behavioral tasks (open-field, object recognition, Y-maze and step-down inhibitory avoidance tasks) from the twelfth day. Na(+), K(+)-ATPase and COX-2 activities were performed in hippocampus and cerebral cortex. aß caused a memory deficit, an inhibition of the hippocampal Na(+), K(+)-ATPase activity and an increase in the hippocampal COX-2 activity. M-NC were effective against all behavioral and biochemical alterations, while M-F restored only the COX-2 activity. In conclusion, M-NC were able to reverse the memory impairment induced by aß, and Na(+), K(+)-ATPase is involved in the effect of M-NC.

Evaluation of the toxicity of α-(phenylselanyl) acetophenone in mice.

Selenium is an essential micronutrient with several biological roles in the human body, but supra nutritional consumption can cause toxic effects. The potential deleterious effects of organoselenium compounds are controversial. The compound α-(phenylselanyl) acetophenone (PSAP) exhibits antioxidant, antidepressant-like and glutathione peroxidase-like activity, which makes important the elucidation of any toxic effects. Hence, the present study aims to investigate the in vitro toxicity of PSAP in Chinese Hamster ovary cells (through MTT assay) and analyse its genotoxicity using the comet assay in mice leukocytes after acute or chronic treatments, alongside with biochemical analyses. Our results demonstrate that the oral administration of PSAP in acute (1, 5, 10, 50, 200 mg/kg) and chronic (1, 10, 50, 200 mg/kg) doses did not cause genotoxicity. The compound presented cytotoxic effect in the MTT assay just at 500 µM after 24 h of administration and at 250 and 500 µM after 48 and 72 h of administration. According to biochemical analysis, PSAP presented a minor toxic effect by altering δ-ALA-D activity in liver and catalase activity in kidney at the highest tested concentration. Taking together, these data indicate that PSAP has low toxic effects after chronic administration in mice.

Essential oil of Psidium cattleianum leaves: antioxidant and antifungal activity.

CONTEXT: Psidium cattleianum Sabine (Myrtacea) is rich in vitamin C and phenolic compounds, including epicatechin and gallic acid as the main components. OBJECTIVE: To evaluate the antifungal and antioxidant capacity in vitro of the essential oil of araçá (EOA). The acute toxicity of the EOA also was evaluated in mice. MATERIALS AND METHODS: The leaves of the P. cattleianum were extracted by steam distillation. The antioxidant capacity was evaluated by in vitro tests [1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), ferric ion reducing antioxidant power (FRAP), linoleic acid oxidation, thiobarbituric acid reactive species (TBARS)], and ex vivo analysis [TBARS, δ-aminulevunilate dehydratase (δ-Ala-D) and catalase activity, non-protein thiols (NPSH), and ascorbic acid levels]. The toxicity was studied in mice by a single oral administration of EOA; and the antifungal activity was performed with five strains of fungi. RESULTS: The EOA exhibited antioxidant activity in the FRAP assay and reduced lipid peroxidation in the cortex (Imax = 32.90 ± 2.62%), hippocampus (IC50 = 48.00 ± 3.00 µg/ml and Imax = 32.90 ± 2.62%), and cerebellum (Imax = 45.40 ± 14.04%) of mice. Acute administration of the EOA by the oral route did not cause toxicological effects in mice (LD50 > 500 µg/ml). The EOA also showed antifungal activity through of the determination minimum inhibitory concentration (MIC) values ranging from 41.67 ± 18.04 to 166.70 ± 72.17 µg/ml for tested strains. CONCLUSION: The results of present study indicate that EOA possess antioxidant properties, antifungal and not cause toxicity at tested doses.

Antinociceptive and anti-hyperalgesic effects of bis(4-methylbenzoyl) diselenide in mice: evidence for the mechanism of action.

CONTEXT: The organoselenium compounds have been described to demonstrate several biological activities, including pain management. OBJECTIVE: This study investigated the antinociceptive, hyperalgesic, and toxic effects of oral administration of bis(4-methylbenzoyl) diselenide (BMD) in mice. MATERIALS AND METHODS: The antinociceptive and anti-hyperalgesic effects of BMD (1, 5, 10, 25, and 50 mg/kg, p.o.) were evaluated using models of nociception: formalin, capsaicin, bradykinin (BK), cinnamaldehyde, phorbol myristate acetate (PMA), 8-bromo-cAM, and glutamate-induced nociception; and mechanical hyperalgesia induced by carrageenan (Cg) or complete Freund's adjuvant (CFA). The acute toxicity was evaluated by biochemical markers for hepatic and renal damages. RESULTS: BMD significantly inhibited the licking time of the injected paw in the early and late phases of a formalin test with ED50 values of 14.2 and 10.8 mg/kg, respectively. This compound reduced nociception produced by capsaicin (ED50 of 32.5 mg/kg), BK (ED50 of 24.6 mg/kg), glutamate (ED50 of 28.7 mg/kg), cinnamaldehyde (ED50 of 18.9 mg/kg), PMA (ED50 of 9.6 mg/kg), and 8-bromo-cAMP (ED50 of 24.8 mg/kg). In the glutamate test, the pretreatment with nitric oxide (NO) precursor, L-arginine, reversed antinociception caused by BMD or N(ω)-nitro-L-arginine (L-NOARG), but the effect of BMD was not abolished by naloxone. Mechanical hyperalgesia induced by Cg and CFA was attenuated by BMD, 70 ± 4% and 65 ± 4%, respectively. Furthermore, a single oral dose of BMD did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels. CONCLUSION: BMD demonstrated as a promising compound because of the antinociceptive and anti-hyperalgesic properties in mice.

Organochalcogen compounds from glycerol: synthesis of new antioxidants.

We describe here a simple method for the synthesis of glycerol derivatives containing an organochalcogen unit (Se, Te and S) using NaBH4 and PEG-400 as a solvent. The new methodology was used to synthesize a range of new organochalcogen compounds in good yields. Furthermore, four of synthesized compounds were evaluated for their antioxidant activity using different assays, such as 2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, nitric oxide (NO) and hydroxyl radical (OH) scavenging, ferric ion reducing antioxidant power (FRAP), ferrous ion chelating, superoxide dismutase-like activity and inhibition of linoleic acid lipid peroxidation. The new organotellurium 2,2-dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3 j showed antioxidant activity and was more effective in inhibition of induced lipid peroxidation compared to solketal 4. Selenium and sulfur analogs 3a and 3m and solketal 4 did not present antioxidant effect. These findings suggest that 2,2-dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3 j is a promising antioxidant and that its activity is influenced by the presence of the tellurium atom on the structure.