RESUMEN
This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl-N'-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action. Using prove of concept in vivo study, we show that dual-targeting compound 7a has a disease-modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Ratas , Animales , Hipoglucemiantes/química , Diabetes Mellitus Tipo 2/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Compuestos de Bifenilo , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Inhibidores Enzimáticos/químicaRESUMEN
Herein we report a study of novel arylchromene derivatives as analogs of naturally occurring flavonoids with prominent α-glucosidase inhibitory properties. Novel inhibitors were identified via simple stepwise in silico screening, efficient synthesis, and biological evaluation. It is shown that 2-aryl-4H-chromene core retains pharmacophore properties while being readily available synthetically. A lead compound identified through screening inhibits yeast α-glucosidase with IC50 of 62.26⯵M and prevents postprandial hyperglycemia in rats at 2.2â¯mg/kg dose.