Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazolin-4(3H)-one derivatives as potential PPARγ and SUR agonists

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19_a, 19_d, 19_f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19_b, 19_d, 19_f, 25_f and 25g exhibited the highest affinities against PPARγ with IC₅₀ values of 0.371, 0.350, 0.369, 0.408 and 0.353µM, respectively. In addition, compounds 19_d, 19_f, and 25_d showed the highest insulin-secreting activities with EC₅₀ values of 0.97, 1.01 and 1.15µM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR.

Keywords: Anti-hyperglycemic; Docking; PPARγ; Pharmacophore; QSAR; Quinazolin-4(3H)-one; Sulfonylurea.