Síntese de 4-(arilcalcogenil)-1H-pirazóis, contendo enxofre ou selênio, a partir de catálise organometálica e avaliação do potencial antioxidante, antinociceptivo e anti-inflamatório

Abstract

Pyrazoles and organochalcogen compounds are organic substances with a wide synthetic and pharmacological potential. This work describes the use of a catalytic system (copper salt and bipyridine) and DMSO as solvent in multicomponent reactions for synthesize several sulfur or selenium-containing 4-(arylchalcogenyl)-1H-pyrazoles, as well as the evaluation of the pharmacological potential of these molecules. Initially, reactions between substituted hydrazines 1a-f with 1,3-diketones 2a-e were made to give the cyclocondensation product 3, and subsequent addition of the arylthiol 4a-g to give a series of 4-(arylthio)-1H-pyrazoles 5a-m from a one pot methodology in good yields (35-89%) at reaction times ranging from 22 to 48h. In addition, from the reactions between substituted hydrazines 1a-f with 1,3- diketones 2a-e and diorganoyl diselenide 6a-g, the 4-(arylselanyl)-1H-pyrazoles 7a-p were obtained from a multicomponent reaction, with good yields (42-98%) in reaction times ranging from 20 to 48 hours. The compounds 3,5-dimethyl-1-phenyl-4-(phenylthio)-1H-pyrazole (5a), 4- (methoxyphenylthio)-3,5-dimethyl-1-phenyl-1H-pyrazole (5k), 4-(4- chlorophenylthio)-3,5-dimethyl-1-phenyl-1H-pyrazole (5m), 3,5-dimethyl-4- (phenylthio)-1H-pyrazole (5o), 3,5-dimethyl-1-phenyl-4-(phenylselenyl)-1Hpyrazole (7a), 3,5-dimethyl-4-(phenylselenyl)-1H-pyrazole (7f), 4- (methoxyphenylselenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (7k) and 4-(4- chlorophenylselenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (7n) had their pharmacological potential explored. In order to investigate the antioxidant capacity of the compounds, neutralization assays of the synthetic radicals 1,1- diphenyl-2-picrylhydrazyl (DPPH), 2,2'-Azinobis-3-ethylbenzothiazoline-6- sulfonic acid (ABTS) and nitric oxide were carried out, as well as the evaluation of the ferric ion reducing potential (FRAP) and lipid peroxidation. Among these tests, compounds 5a and 7a showed promising effects in vitro. The evaluation of the antinociceptive activity of compounds 3a (3,5-dimethyl-1fenil-1Hpyrazole, without organochalcogen group), 5a and 7a was performed in the nociception models induced by formalin, glutamate and hot plate in mice. Meanwhile, the anti-inflammatory activity was evaluated according to models of induction of edema by formalin and chroton oil. In both cases, compounds 5a and 7a, containing an organic group of sulfur and selenium, respectively, presented superior effects when compared to the control group and to compound 3a. Moreover, acute toxicity experiments showed no evidence of toxicity from treatment with compounds 3a, 5a and 7a when given at high doses (300 mg/kg) in mice. In this sense, according to the present work, it can be concluded that 4-(arylcalcogenyl)-1H-pyrazoles can be obtained from simple and efficient methodologies, and that they present antioxidant, antinociceptive and anti-inflammatory activities.