Elucidação estrutural e avaliação do potencial biológico de novos derivados N-acilhidrazônicos

Abstract

The N-acylhydrazone functionality has been reported as the pharmacophoric group of compounds with a wide variety of biological properties, including anti-inflammatory, analgesic and antimicrobial activities. The objective of this study was to elucidate structurally and to evaluate the analgesic, anti-inflammatory and antimicrobial potential of N- acylhydrazone derivatives (JR04, JR09 and JR19). The previously synthesized compounds were physico-chemically characterized and the structural elucidation was performed by spectroscopic and spectroscopic techniques. In the pharmacological tests Swiss adult albino mice of both sexes were used. The models used for anti-inflammatory activity were: peritonitis and paw edema induced by carrageenan, and pockets of subcutaneous air. For the antinociceptive potential was performed: formalin-induced nociception and orofacial pain induced by formalin. The acute toxicity test was also performed. In the microbiological assays American Type Culture Collection (ATCC) standard bacterial and fungal strains were used by disc diffusion and microdilution methods. The compounds showed yields above 50%. Regarding the melting range, the temperature variation for most compounds was up to 3° C. All compounds presented LogP <5, being in agreement with the rule of Lipinsk, and chemical displacement signals characteristic of the proposed struct ures as being (2-cyano-N'-[4-(methylsulfonyl) benzylidene] acetohydrazide (JR04), '-(benzylidene)-2-cyanoacetohydrazide (JR09) and N'-[(1-H-indol-3-yl)methylene]-2-cyanoacetohydrazide (JR19) in RMN of 1H and RMN of 13C DEPT-Q spectra. In the carrageenan-induced peritonitis model, oral administration of the compounds JR04 (10 and 20mg/kg), JR09 (20mg/kg) and JR19 (10 and 20mg/kg) inhibited significantly at 48, 54, 61, 59 and 52%, respectively, leukocyte migration when compared to the control group, and there was no significant difference between doses of 10 and 20 mg/Kg of JR04 and JR19. The dose of 10mg/kg was selected for the other tests. In the pockets of subcutaneous air, all compounds significantly inhibited cell migration when compared to the negative control, at 55, 52 and 66%, for JR04, JR09 and JR19, respectively. They also reduced carrageenan-induced paw edema, especially compounds JR19. Confirming the anti-inflammatory activity in paw edema, the compounds significantly reduced serum C-reactive protein (CRP) concentration when compared to the control group. In the models of formalin-induced nociception and orofacial pain induced by formalin, compounds JR09 and JR19 were active only in the second phase, suggesting to be devoid of central analgesic effect and possibly anti-inflammatory action retainer. The compound JR04 increased the reactivit y time in the two phases in these models, this is suggestive of an increase in the synthesis and/or initial release of BK promoting an intensification of action of this vasoactive peptide. In the evaluation of the acute toxicity of compounds JR09 and JR19 at the dose of 100mg/Kg there was no death or behavioral or physiological changes, indicating low toxicity of the molecules tested. In the tests of antimicrobial activit y, no inhibition of the growth of the tested microorganisms was observed, indicating absence of antimicrobial activit y, by the methods used. The results indicate the effectiveness of the N-acylhydrazone derivatives as anti-inflammatory, favoring H and RMN of C DEPT-Q spectra. In the carrageenan-induced the prospects for its future use with this therapeutic objective.