Avaliação da toxicidade e investigação dos efeitos anti-inflamatórios e antinociceptivos in vivo de derivados isatinas-tiosemicarbazonas

Abstract

Isatine-thiosemicarbazone derivative compounds are chemicals originating from the condensation of isatins with thiosemicarbazides and have several applications in therapeutics, such as in the treatment of smallpox, virus inhibition, antitumor, antifungal, antibacterial and antimalarial activities. The objective of this work was to evaluate the in vivo anti-inflammatory and antinociceptive activities of IsatineThiosemicarbazones (PA-Int4: (Z)-2-(2-oxoindolin-3-ylidene)-Nphenylhydrazinecarbothioamide and PA-Int5: (Z)-2-(5-nitro-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide). Swiss mice of both genders were used. The acute toxicity evaluation, and the subchronic toxicity evaluation was performed with at the doses of 1; 2.5 and 5 mg/kg. The animals were also submitted to central neural evaluation by the open field and rotarod tests. The anti-inflammatory activity was evaluated by the paw edema and air bag test (5 animals/group), analgesic activity was evaluated through abdominal contortion test and formalin test, also using the doses of 1; 2.5 and 5 mg/kg orally. In acute toxicity there was a significant difference in the concentration of glucose, urea and hemoglobin for PA-Int5 treated females. In the subchronic toxicity, it presented alterations in the triglycerides, AST and platelet count for groups treated with PA-Int4; and in the dosages of triglycerides, total cholesterol and hemoglobin from groups treated with doses of PA-Int5. Regarding the evaluation of the anti-inflammatory activity, in the paw edema model, PA-Int4 compound reduced edema by up to 70%, and PA-Int5 presented 56% of edema reduction, both from the first hour, mainly in the dose 5 mg/kg. Anti-inflammatory activity was also observed in the air pocket test, with inhibition of leukocyte migration by up to 73 and 66% for PA-Int4 and PA-Int5, respectively; as well as the reduction of pouch proteins, in 81 and 72%, respectively, for PA-Int4 and PA-Int5. The analgesic activity through the abdominal contortion test demonstrated action with a reduction in contortion of up to 39% and 34%, respectively, for PA-Int4 and PA-Int5. Through the formalin test, the compound presented analgesic activity in the stage of inflammatory pain, with reduction of the pain response in up to 77 and 88% for PA-Int4 and PA-Int5. Our results suggest that compounds PA-Int4 and PA-Int5 may be considered good candidates for drugs, fueling the prospect of technological innovation in the discovery of new drugs.