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-dimethyl1-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 -azinobis(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 [delta]-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. Key words: antioxidant, organoselenium, oxidative stress, toxicity, pyrazoles. Les pyrazoles representent une importante classe de composes heterocycliques dotes de proprietes pharmacologiques. La presente etude portait sur le potentiel antioxydant de composes derives des pyrazoles dans le cerveau de souris in vitro et sur l'effet des composes derives des pyrazoles sur les parametres des dommages et de la toxicite lies a l'oxydation dans le cerveau et le plasma de souris. Les composes evalues etaient les suivants : 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazole (1a), 3,5-dimethyl-4-(phenylselanyl)-1H-pyrazole (2a), 4-((4-methoxyphenyl)selanyl)- 3,5-dimethyl-1-phenyl-1H-pyrazole (3a), 4-((4chlorophenyl)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) et 3,5-dimethyl-1-phenyl-1H-pyrazole (1c). In vitro, les 4- (arylcalcogenyl)1H-pyrazoles, dans des proportions moleculaires faibles, entrainaient une diminution des taux de peroxydation lipidique et de derives reactifs dans des homogenats de cerveaux de souris. Les composes presentaient aussi une capacite de reduction ferrique, ainsi que de piegeage de l'oxyde nitrique. En particulier, les composes 1a, 1b et 1c affichaient une activite de piegeage efficace du 1,1-diphenyl-2-picryl-hydrazyle. Les composes 1b et 1c affichaient une activite de piegeage du 2,20-azino-bis (3-ethylbenzthiazoline-6-acide sulfonique). Les epreuves in vivo ont montre que les composes 1a, 1b et 1c (a 300 mg/kg, avec administration unique par voie intragastrique) n'ont pas entraine de diminution de l'activite de la dehydratase de l'acide [delta]-aminolevulinique, une enzyme qui presente une sensibilite elevee en situation de pro-oxydation, dans le cerveau, le foie et les reins de souris. Le compose 1c entrainait intrinsequement une diminution de la peroxydation lipidique dans le cerveau et le foie de souris. Les epreuves toxicologiques montrent que les composes 1a, 1b et 1c ne presentent pas de toxicite quant a l'aspartate aminotransferase et a l'alanine aminotransferase ainsi qu'aux taux d'uree et de creatinine dans le plasma. En conclusion, les resultats ont montre l'activite antioxydante de composes derives des pyrazoles dans le cadre d'epreuves in vitro. En outre, les resultats ont montre la faible toxicite des composes dans le cadre d'epreuves in vivo. Mots-des : antioxydant, organoselenium, stress oxydatif, toxicite, pyrazoles.
Introduction Pyrazole, a five-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions (Fig. 1), is reported to possess a wide range of biological activities [...]