RESUMO
Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated. The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase. Almost all the compounds had strong inhibitory activities against yeast α-glycosidase. Regarding rat intestinal α-glycosidase, only analogs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal maltase and lactase and nearly all compounds showed no inhibition against rat intestinal α-amylase. Structure-activity relationship studies indicated that 5-(p-toluenesulfonylamino)phthalimide moiety is a favorable scaffold to exert the α-glucosidase inhibitory activity and substituents at the N2 position have considerable influence on the efficacy of the inhibition activities.
Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Ftalimidas/farmacologia , Compostos de Tosil/farmacologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores de Glicosídeo Hidrolases , Glicosídeo Hidrolases/metabolismo , Intestinos/enzimologia , Modelos Moleculares , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Ratos , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade , Compostos de Tosil/síntese química , Compostos de Tosil/química , alfa-Glucosidases/metabolismo , beta-Galactosidase/antagonistas & inibidores , beta-Galactosidase/metabolismoRESUMO
A series of N-substituted 1-aminomethyl-ß-d-glucopyranoside derivatives was prepared. These novel synthetic compounds were assessed in vitro for inhibitory activity against yeast α-glucosidase and both rat intestinal α-glucosidases maltase and sucrase. Most of the compounds displayed α-glucosidase inhibitory activity, with IC50 values covering the wide range from 2.3µM to 2.0mM. Compounds 19a (IC50=2.3µM) and 19b (IC50=5.6µM) were identified as the most potent inhibitors for yeast α-glucosidase, while compounds 16 (IC50=7.7 and 15.6µM) and 19e (IC50=5.1 and 10.4µM) were the strongest inhibitors of rat intestinal maltase and sucrase. Analysis of the kinetics of enzyme inhibition indicated that 19e inhibited maltase and sucrase in a competitive manner. The results suggest that the aminomethyl-ß-d-glucopyranoside moiety can mimic the substrates of α-glucosidase in the enzyme catalytic site, leading to competitive enzyme inhibition. Moreover, the nature of the N-substituent has considerable influence on inhibitory potency.