Avaliação da atividade anti-inflamatória, toxicidade in vivo e in vitro e possíveis mecanismos de ação do composto 2-ciano-N-3-difenilacrilamida (JPMR-01)

Abstract

Inflammation is a crucial process for the body's defense, however, when there is an exacerbation or prolongation of the inflammatory stimulus, it begins to induce tissue damage, which can culminate in chronic inflammatory diseases. In these situations, it is necessary to intervene in the inflammatory response. Currently available anti-inflammatory drugs lead to undesirable adverse reactions, such as gastric ulcers and cardiovascular events. To reduce such effects, we seek to develop new chemical compounds that have enhanced therapeutic effects and reduced adverse events. For this purpose, the compound 2-cyano-N-3-diphenylacrylamide (JMPR-01) was synthesized, and preliminary tests demonstrated a potential anti-inflammatory effect. Therefore, the main objective of this work was to evaluate the anti-inflammatory and toxicological activity of the compound JMPR-01. To this end, in vivo, inflammatory models were carried out, in which the efficacy of JMPR-01 on the compound's antiedematogenic activity was investigated, using the zymosan induced paw edema model, JMPR-01 was able to significantly reduce paw edema (p< 0.05) at all doses tested (50, 100 and 150 mg/Kg), from this test it was possible to establish the dose to be used in the other tests (50 mg/Kg). In the paw edema test with inhibitors of the enzyme nitric oxide synthase and soluble guanylate cyclase, it was observed that JMPR-01 was not able to inhibit edema, suggesting a possible involvement of this via in the mechanism of action. In the subcutaneous air pocket test, the compound administered at doses of 50 mg/kg and 100 mg/kg was able to reduce leukocyte migration by 76% and 62%, respectively. In vitro, the compound was also effective in inhibiting the hyaluronidase enzyme against Bothrops erythromelas (PBe) snake venom. The toxicity of the compound was also evaluated, in vitro, the percentage of hemolysis in erythrocytes was 1.6 and 1.26% at concentrations of 500 and 1,000 μg/mL of JMPR-01, respectively. In vivo, the single dose acute toxicity test (2,000 mg/Kg) did not demonstrate clinical signs of toxicity, there were also no deaths or behavioral changes in the animals, in addition to there being no macroscopic changes in the organs analyzed, demonstrating the low toxicity of the compound. The molecular docking studies carried out demonstrated a greater affinity of the JMPR-01 compound for the soluble guanylate cyclase enzyme. These results indicate the effectiveness of the anti-inflammatory properties of the compound JMPR-01 with prospects for the development of a new drug with a potential inhibitor of the via NO-sGC-cGMP.