Angélica S. Reis

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

ABSTRACT 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. HighlightsPSOQ exerts antinociceptive and anti‐inflammatory effects.PSOQ did not cause gastrointestinal ulceration and sedative effects.PSOQ suppressed the severity of croton oil via inhibition of MPO activity.

Further analysis of acute antinociceptive and anti-inflammatory actions of 4-phenylselenyl-7-chloroquinoline in mice

A new quinoline containing selenium, 4‐phenylselenyl‐7‐chloroquinoline (4‐PSQ), was described and synthetized by our research group. Recently, we demonstrated the potential antinociceptive and anti‐inflammatory of 4‐PSQ. For this reason, the first objective of this study was to expand our previous findings by investigating the contribution of glutamatergic, serotonergic, and nitrergic systems to the acute antinociceptive action of this compound. Pretreatment with 4‐PSQ (0.01–25 mg/kg, p.o.) reduced the nociception induced by glutamate. MK‐801 (an uncompetitive antagonist of the N‐Methyl‐d‐aspartate (NMDA) receptor) blocked the antinociceptive effect exerted by 4‐PSQ (25 mg/kg, p.o.) in the acetic acid‐induced abdominal writhing test. The pretreatment with WAY100635 (a selective antagonist of 5‐HT1A receptor), ketanserin (a selective antagonist of 5‐HT2A/2C receptor), and pindolol (a nonselective antagonist of 5‐HT1A/1B receptors) partially blocked the antinociceptive effect caused by 4‐PSQ (25 mg/kg, per oral, p.o.) in the acetic acid‐induced abdominal writhing test. Nitric oxide precursor, l‐arginine hydrochloride, partially reversed antinociception caused by 4‐PSQ or ω‐nitro‐l‐arginine (l‐NOARG). Treatments did not modify the locomotor and exploratory activities of mice. Additionally, the acute anti‐inflammatory effect of 4‐PSQ in a model of pleurisy induced by carrageenan in mice was investigated. 4‐PSQ reduced the cellular migration, pleural exudate accumulation, and myeloperoxidase activity induced by carrageenan exposure. 4‐PSQ protected against the increase in reactive species levels and reduction of nonprotein thiol levels induced by carrageenan. Data presented here showed that the modulation of serotonergic, nitrergic, and glutamatergic systems contributed to the antinociceptive effect of 4‐PSQ and it reinforced the therapeutic potential of this quinolinic compound for acute inflammation.

Antioxidant effect of quinoline derivatives containing or not selenium: Relationship with antinociceptive action quinolines are antioxidant and antinociceptive

The present study investigated the antioxidant effect of a new class of quinoline derivatives (a-d) on assays in vitro. Lipid peroxidation, thiol peroxidase-like and free radical scavenging activities were determined to evaluate antioxidant activity of compounds. Thiol oxidase-like and δ-aminolevulinate dehydratase activities were performed as a toxicological parameter. A second objective of this study was to evaluate the in vivo antinociceptive effect of the compound with better antioxidant effect and without toxic effects in a model of nociception induced by formalin in mice. In liver, at 100 µM, compound a reduced the lipid peroxidation to the control levels, while compounds c and d partially reduced it. In brain, only compound d partially reduced the lipid peroxidation at 50 and 100 µM. Compound b did not have an effect on the lipid peroxidation. Thiol peroxidase-like and free radical scavenging activities are not involved in the antioxidant mechanisms of these compounds. Compounds did not present thiol oxidase-like activity and effect on the δ-aminolevulinate dehydratase. In vivo experiments showed that compound a caused an inhibition of licking time in the first and second phases, and edema formation induced by formalin. In conclusion, quinoline derivative without selenium presented better in vitro antioxidant effect and in vivo antinociceptive activity.

Antinociceptive property of vinyl sulfides in spite of their weak antioxidant activity

Vinyl sulfides (a–c), a new class of organosulfur compounds, were screened for antioxidant and antinociceptive activities. In view of this, in vitro antioxidant effect was investigated through the determination of the thiobarbituric acid reactive substances and protein carbonyl levels in rat brain homogenate. Considering the results obtained in vitro, antinociceptive activity of vinyl sulfides (a–c) (5–50 mg/kg, intragastrically) was investigated in a model of nociception induced by glutamate (20 μmol/paw, 20 μl, intraplantar) in mice. A close inspection of the results revealed that unsymmetrical substituted vinyl sulfides (compounds a–c) presented weak antioxidant activity against lipid peroxidation and protein carbonilation in vitro. In vivo experiments showed that compounds a, b, and c, at all doses (5–50 mg/kg), caused an inhibition of the licking and edema induced by glutamate in mice. However, antinociceptive action of sulfides was not dose-dependent, as well as the antioxidant effect was not concentration-dependent. Thus, chemical structure of vinyl sulfides is not related with pharmacological effects. The results demonstrated that vinyl sulfides presented weak antioxidant effect and potent antinociceptive and antiedematogenic effect.

The efficacy of microemulsion-based delivery to improve vitamin E properties: evaluation of the antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice

A microemulsion‐based delivery system was designed to improve vitamin E (VE) properties, and its antinociceptive, antioxidant, antidepressant‐ and anxiolytic‐like activities in mice were evaluated.

Current advances of pharmacological properties of 7-chloro-4-(phenylselanyl) quinoline: Prevention of cognitive deficit and anxiety in Alzheimer’s disease model

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) at a dose of 1 mg/kg in memory impairment and anxiety in an Alzheimers disease (AD) model induced by amyloid β-peptide (Aβ) (fragment 25-35) in mice. The involvement of acetylcholinesterase (AChE) activity and lipid peroxidation in hippocampus and cerebral cortex was evaluated. Male Swiss mice were pretreated with 4-PSQ (1 mg/kg, intragastrically (i.g.), daily) for fourteen days. Thirty minutes after the first treatment with 4-PSQ, the animals received a single injection of Aβ (3 nmol/3 μl/per site, intracerebroventricular (i.c.v.)). Mice were submitted to the behavioral tasks (open-field, elevated plus maze, Barnes maze, object recognition and location, and step-down inhibitory avoidance tests) from the fifth day onwards. On the fifteenth day, blood was removed for analysis of biochemical markers (glucose, triglycerides, urea, aspartate (AST) and alanine (ALT) aminotrasferases), and cerebral cortex and hippocampus for determination of AChE activity and thiobarbituric acid reactive species (TBARS) levels. Aβ caused memory impairment, anxiogenic behavior, increased AChE activity in the cerebral structures and TBARS levels in the cerebral cortex. 4-PSQ was effective to protect against behavioral changes, AChE activity and TBARS levels. In conclusion, 4-PSQ protected against learning and memory impairment and anxiety in a mouse model of AD induced by Aβ, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound.

Synthesis and Pharmacological Evaluation of Novel Selenoethers Glycerol Derivatives for the Treatment of Pain and Inflammation: Involvement of Nitrergic and Glutamatergic Systems

AbstractIn the present study, the synthesis of new selenoethers from nucleophilic substitution reaction between organyl halides and nucleophilic species of selenium generated in situ was demonstrated. After, this method was applied for the synthesis of pyridylselenides glycerol derivatives 9b and 9c and the antinociceptive and anti-inflammatory effects, as well as, acute toxicity were evaluated. In the formalin test, the compound 9b caused a reduction in licking time in both phases. Compounds 9b and 9c increased the latency to response in the hot-plate test and reduced the licking time induced by glutamate. Our results revealed the involvement of the nitrergic and/or glutamatergic pathways in the antinociceptive action of the compounds. Additionally, 9b and 9c did not cause any toxicity signals and oxidative stress parameters were not modified by treatments. Here, it was developed an alternative and efficient method for the synthesis of selenoethers glycerol derivatives. Furthermore, we demonstrated that this class is indeed interesting for the research of new drugs. Graphical Abstractᅟ