Sahar M. Abou-Seri, AlShaimaa M. Taha, Mona A. Mohamed* and Nour M. Abdelkader Pages 632 - 645 ( 14 )
Background: Sulphonylureas are the oldest and commonly used to treat diabetic patients, but its efficacy declines by time. It was reported that quinazoline nucleus exhibits a potent hypoglycemic effect in diabetic animal models.
Objective: The current study aimed to synthesize new quinazoline-sulfonylurea conjugates and evaluate their hypoglycemic effects in alloxan-induced diabetic rats.
Method: The conjugates were synthesized by bioisosteric replacement of 5-chloro-2-methoxybenzamide moiety in glibenclamide or 1,3-dioxo-3,4-dihydroisoquinoline moiety in gliquidone with 6,7-dimethoxy-4-oxoquinazoline moiety (compounds 4a-4d, 9b-9c and 10b-10d). Diabetes was induced in rats by a single i.p. administration of alloxan, followed by treatment with the synthesized conjugates (5mg/kg b.w.).
Results: All conjugates showed hypoglycemic effects with different efficacy indicated by the reduction in blood glucose and elevation of insulin levels. Moreover, these conjugates up-regulated the expression of pancreatic GLUT2, muscle GLUT4, and IRS-1 genes, compared to the diabetic group. A normal pancreatic tissue pattern was noticed in diabetic rats treated with compounds 9b, 9c, and 10c.
Conclusion: Conjugation of sulfonylurea with quinazoline (especially 9b, 9c, 10c) possessed a significant hypoglycemic effect through improving blood insulin level and insulin action and consequently increased the glucose uptake by the skeletal muscles.
Sulfonylurea, quinazoline, bioisoster, hypoglycemic, Insulin Receptor Substrate-1.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Biochemistry Division, Department of Chemistry, Faculty of Science, Al-Azhar University, Cairo, Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo