Obtenção de uma nova carboximidamida com propriedades antidiabéticas e anti-inflamatórias

Abstract

Diabetes mellitus is metabolic alteration which involves the metabolism of carbohydrates, resulting in decrease of peripheral tissues response to insulin and increased glycemia, which leads to complications such as nephropathy, neuropathy and retinopathy. In addition, it is associated with modification of the immune response, leading in increased production of inflammatory mediators, triggering chronic inflammation. Natural products are sources of new antidiabetic and anti-inflammatory drugs, thus being fundamental for the development of prototypes that may serve as a basis for drugs development in the future. The aim of this work was synthesize a new derivative from reaction between naringenin and aminoguanidine and to elucidate its anti-diabetic and anti-inflammatory properties. The condensation reaction between aminoguanidine and naringenin produced a derivative characterized as a hydrazine carboximidamide (DCHA) in a post-reaction yield of 81%. DCHA was chemically characterized by mass spectrometry, NMR and IV. The DCHA didn’t exhibited toxicity in murine fibroblasts up to 50 ug / ml. The DCHA demonstrated antioxidant activity upper to naringenin and satisfactory glycation inhibition in vitro. In silico assays. DCHA showed affinity to iNOS, COX and PDE4, thus suggesting that molecule could exhibit anti-inflammatory and hypoglycemic activities. In the antidiabetic activity tests, DCHA decreased the glycemic levels of diabetic mice after 21 days of oral treatment (30mg / kg), thus wielding a hypoglycemic effect. In the anti-inflammatory activity assays, DCHA showed a significant anti-inflammatory response by suppressing the leukocytes migration into the peritoneal cavity in LPS-mice exposed and treated at a dose of 1mg / kg, inhibiting the activation of macrophages in vitro and decreasing edema in a model of zimozan-induced arthritis in mice when treated orally (5 mg / kg). The results obtained demonstrate that it was possible to obtain a new chemical entity from reaction between naringenin and aminoguanidine with antioxidative, hypoglycemic and anti - inflammatory activity which can be further explored in the development of a prototype for treatment of chronic diseases such as diabetes or other processes inflammatory drugs.