Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives of carbohydrates as alpha-glucosidases inhibitors.
A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-D-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.
Ferreira
Sabrina B
SB
Instituto de Química, Universidade Federal do Rio de Janeiro, LABRMN, Ilha do Fundão, 21949-900 Rio de Janeiro, Brazil.
Sodero
Ana C R
AC
Cardoso
Mariana F C
MF
Lima
Emerson S
ES
Kaiser
Carlos R
CR
Silva
Floriano P
FP
Ferreira
Vitor F
VF
D000595:Amino Acid Sequence; D001665:Binding Sites; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry*; D002384:Catalysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D015003:Yeasts / Q000201:enzymology / Q000235:genetics; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D065089:Glycoside Hydrolase Inhibitors; D014230:Triazoles; D000520:alpha-Glucosidases