RESUMO
Type 2 diabetes mellitus is a complex metabolic disorder requiring polypharmacology approaches for effective treatment. Combinatorial library of fifteen new tricyclic benzimidazole derivatives have been designed and synthesized to combine fragments commonly found in allosteric AMPK activators and AT1 receptor antagonists. It was found that 2'-cyanobiphenyl serves as the pharmacophore of AMPK-activating activity, which also increases with the expansion of the external hydrogenated cycle. Also, pronounced antiplatelet activity is characteristic of the studied compounds. One of derivatives was identified as a potent inhibitor of the formation of advanced protein glycation end-products with reactive dicarbonyl scavenging activity. Two submicromolar AMPK activators 2b and 3b prevents inflammatory activation of murine macrophages. Along with good water solubility and synthetic availability, these results render biphenyl derivatives of fused benzimidazoles as a valuable starting point for the development of AMPK activators with multi-target antidiabetic activity.
Assuntos
Proteínas Quinases Ativadas por AMP/química , Benzimidazóis/química , Ativadores de Enzimas/química , Hipoglicemiantes/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/química , Bovinos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Avaliação Pré-Clínica de Medicamentos , Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Glicosilação/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Soroalbumina Bovina/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Prevention of the formation of advanced glycation end-products (AGEs) is a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In these terms, new synthetic approaches to 6-nitroazolo[1,5-a]pyrimidines have been developed on the basis of the promising antiglycation activity of their structural analogues, such as azolo[5,1-c][1,2,4]triazine-4(1H)-ones. A number of nitroazolopyrimidines were obtained by using nitration, chlorodeoxygenation, and amination reactions, and their antidiabetic properties were elucidated in vitro. It was shown that triazolo[1,5-a]pyrimidine-7(4H)-ones exhibit a higher antiglycation activity than the corresponding 7-alkylamino analogs and aminoguanidine, as the reference compound. It is suggested that this kind of activity can be associated with the chelating properties possessed by the synthesized 6-nitro-7-oxoderivatives. Furthermore, the compounds obtained were tested for their inhibitory activity against dipeptidyl peptidase 4 (DPP4), glycogen phosphorylase, and α-glucosidase in vitro, but their activities proved to be significantly inferior to those of the reference compounds.
