Ethel A. Wilhelm

Organocatalytic synthesis and evaluation of 7-chloroquinoline-1,2,3-triazoyl carboxamides as potential antinociceptive, anti-inflammatory and anticonvulsant agent

We describe herein our results on the organocatalytic synthesis and pharmacological properties of 7-chloroquinoline-1,2,3-triazoyl carboxamides. This class of compounds was synthesized in good to excellent yields by the reaction of 4-azido-7-chloroquinoline with a range of β-oxo-amides in the presence of a catalytic amount of pyrrolidine (5 mol%). The obtained compound 3a was screened for anticonvulsant, antinociceptive and anti-inflammatory activities in vivo. The results demonstrated that compound 3a was effective in decreasing the appearance of seizures induced by pilocarpine and pentylenetetrazole. In addition, compound 3a demonstrated antinoceptive and anti-inflammatory properties for combating acute pain. This protocol is an efficient method for the production of new heterocyclic compounds with pharmacological activities.

Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test.

Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demonstrated a role for selenium in mood disorders. For this reason, the present study investigated the role of the monoaminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001–10 mg/kg) was administered orally (p.o.) 30 min prior to testing, and all of the tested doses reduced the immobility time in the TST without changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the TSTwas prevented by pre-treatment in mice with ketanserin (1 mg/kg, intraperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist),WAY100635 (0.1mg/kg, subcutaneous (s.c.); a selective 5-HT1A receptor antagonist), p-chlorophenylalaninemethyl ester-PCPA (100mg/kg, i.p.; a selective inhibitor of tryptophan hydroxylase), prazosin (1 mg/kg, i.p.; an α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p.; an α2-adrenoceptor antagonist), SCH233390 (0.05 mg/kg, s.c., a dopaminergic D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopaminergic D2 receptor antagonist), but not with ondansetron (1 mg/kg, i.p.; a selective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressant like effect in TST at lower doses (0.001–10 mg/kg), which is dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems.

Meloxicam-loaded nanocapsules have antinociceptive and antiedematogenic effects in acute models of nociception.

AIMS The development of new treatments for inflammation and pain continues to be of high interest, since long-acting effect is critical for patients. The present study investigated whether the polymeric nanocapsules, a drug delivery system, have pharmacological effect on acute nociceptive and inflammatory models in mice. MAIN METHODS Swiss mice (20-25 g) were previously pre-treated with meloxicam-loaded nanocapsules (M-NC) or free meloxicam (M-F) or suspension without drug (B-NC), at a dose of 5 mg/kg (per oral) at different times (0.5-120 h). Antinociceptive and antiedematogenic effects were evaluated by chemical (acetic acid-induced abdominal writhing, nociception and paw edema induced by formalin and glutamate, croton oil-induced ear edema) and thermal (tail immersion and hot-plate) tests. KEY FINDINGS M-NC reduced the licking time- and paw edema-induced by glutamate and formalin, while M-F did not have an effect. In the acetic acid-induced abdominal writhing and croton oil-induced ear edema, analysis of time-course revealed that M-NC showed a response more prolonged than M-F. In the hot-plate test, a thermal test, the time-course analysis indicated a similar increase in the latency response to thermal stimuli of M-NC and M-F, while in the tail-immersion test M-F had an effect at 0.5 h and M-NC at 24 h. SIGNIFICANCE Polymeric nanoparticles had antinociceptive, anti-inflammatory and antiedematogenic effects in the formalin and glutamate tests, and prolonged the effect in acetic acid and croton oil tests, but not in thermal tests, supporting the idea that the inflammatory process in tissues facilitates the vectoring of polymeric nanoparticles.

Chitosan/poly(vinyl alcohol)/bovine bone powder biocomposites: A potential biomaterial for the treatment of atopic dermatitis-like skin lesions.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects a large percent of the world́s population. This long-lasting skin disease has been treated by different approaches according to its causative agent and severity. Nonetheless, the use of advanced biomaterials to treat AD is poorly explored. The present study assessed the protective effectiveness of biocomposites films based on chitosan (Cs), poly(vinyl alcohol) (PVA) and bovine bone powder (BBP) on AD-like skin lesions. These original biocomposites were fully characterized and in vivo biological assays concerning the AD treatment were performed using a mouse model induced by 2,4-dinitrochlorobenzene (DNCB). The dorsal skin and ear of Balb/c female mice were challenging cutaneously with DNCB. Our findings demonstrate BBP-based biocomposite attenuated and treated considerably the DNCB-induced skin lesions in an AD-like model. In this sense, this study suggests that this original biocomposite may be applied as an active biomaterial for AD treatment.

7-Chloroquinoline-1,2,3-triazoyl Carboxylates: Organocatalytic Synthesis and Antioxidant Properties

We describe herein our results on the synthesis and antioxidant properties of 7-chloroquinoline-1,2,3-triazoyl-4-carboxylates. This class of compounds have been synthesized in moderated to excellent yields by the reaction of 4-azido-7-chloroquinoline with a range of β-ketoesters in the presence of a catalytic amount of pyrrolidine (10 mol%). The synthesized compounds ethyl 1-(7-chloroquinolin-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylate and ethyl 1-(7-chloroquinolin-4-yl)-5-phenyl-1H-1,2,3-triazole-4-carboxylate were screened for their in vitro antioxidant activity and the results demonstrated that the first compound reduces the lipid peroxidation levels induced by sodium nitroprusside in liver of mice, while the second compound shown nitric oxide scavenging activity. This is an efficient method to produce new heterocyclic compounds with potential antioxidant activities.

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.

Contribution of dopaminergic and noradrenergic systems in the antinociceptive effect of α-(phenylalanyl) acetophenone

BACKGROUND This study evaluated the antinociceptive action of α-(phenylalanyl) acetophenone (PSAP) in mice. METHODS Evaluated whether the serotonergic, adrenergic and dopaminergic systems are involved in PSAP antinociceptive activity. PSAP was administered intragastrically (ig) 30min prior to formalin or glutamate test and compared with a standard drug, meloxicam (10mg/kg, ig). RESULTS The treatment with PSAP (10-50mg/kg) caused inhibition in the neurogenic phase and reduced the paw oedema caused by intraplantar (ipl) injection of formalin. PSAP (1-50mg/kg) decreased the nociceptive response in the inflammatory phase of the formalin test and in licking behaviour triggered by glutamate at doses of 0.1-50mg/kg. The antinociceptive effect of PSAP (1mg/kg) was abolished when the animals were pre-treated with prazosin (α1-adrenergic antagonist receptor, 0.15mg/kg, intraperitoneally, ip), yohimbine (α2-adrenergic antagonist receptor, 1mg/kg, ip) and sulpiride (D2/D3 dopamine antagonist, 5mg/kg, ip). The antinociceptive effect of PSAP (1mg/kg) was not abolished by WAY100635 (5-HT1A-selective serotoninergic antagonist, 0.7mg/kg, ip), ketanserin (selective antagonist of serotonergic 5-HT2A/2C, 0.3mg/kg, ip), ondansetron (5-HT3 selective serotoninergic antagonist, 0.5mg/kg, ip) or SCH23390 (D1 dopamine receptor antagonist, 0.05mg/kg, ip) in the glutamate test. No changes in locomotor activity were observed in the animals treated with PSAP and/or antagonists in the open field test. CONCLUSION These results showed the antinociceptive action of PSAP in formalin and glutamate tests and the involvement of the dopaminergic and adrenergic systems in its antinociceptive activity.

Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-β 1–42 peptide in mice

&NA; An increasing body of evidence indicates that the activation of indoleamine‐2,3‐dyoxigenase (IDO), a first and rate‐limiting enzyme in the kynurenine (KYN) pathway, is involved in A&bgr;1–42‐neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to A&bgr;1–42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of A&bgr;1–42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety‐like behaviour in the elevated plus‐maze and open field tests after the A&bgr;1–42 administration. Aged mice also responded to A&bgr;1–42 with a higher deficiency of brain‐derived neurotrophic factor, glutathione levels and total radical‐trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of A&bgr;1–42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin‐6, lower levels of interleukin‐10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age‐associated inflammatory signature and down‐regulation of neuroprotectants in the brain render aged mice more vulnerable to A&bgr;1–42‐induced memory loss, anxiety symptoms and KYN pathway dysregulation. HighlightsIndoleamine‐2,3‐dioxigenase mediates behavioural disturbances induced by A&bgr;1–42.Aging exacerbates A&bgr;1–42‐induced cognitive and anxiety deficits.Aging aggravates A&bgr;1–42‐mediated neuroinflammation.Aging aggravates BDNF and antioxidant deficiency elicited by A&bgr;1–42.Aging further increase KYN dysregulation in brain of A&bgr;1–42‐treated mice.

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.

Organoselenium compounds from purines: Synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities and memory improvement effect

We describe here a simple method for the synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities, and memory improvement effect. This class of compounds was synthesized in good yields by a reaction of 6-chloropurine with diaryl diselenides using NaBH4 as reducing agent and PEG-400 as solvent. Furthermore, the synthesized compounds were evaluated for their in vitro antioxidant and acetylcholinesterase (AChE) inhibitor activities. The best AChE inhibitor was assessed on the in vivo memory improvement. Our results demonstrated that the 6-((4-chlorophenyl)selanyl)-9H-purine and 6-(p-tolylselanyl)-9H-purine presented in vitro antioxidant effect. In addition, 6-((4-fluorophenyl)selanyl)-9H-purine inhibited the AChE activity and improved memory, being a promising therapeutic agent for the treatment of Alzheimers disease.