Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of phthalimide-sulfonylurea hybrids as PPARγ and SUR agonists

New series of phthalimide-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds 6(c), 6(d), 6(g), 6(h), 6(j) and 6(k) induced significant reduction in the blood glucose levels of diabetic rats ranging from 24.43 to 21.43%. Moreover, molecular docking and pharmacophore approaches were carried out to examine binding modes and fit values of the prepared compounds against PPAR gamma and SUR, respectively. Compounds 6(c), 6(d), 6(j) and 6(m) exhibited the highest binding free energies against PPAR gamma. Compounds 6(c), 6(j), 6(k), 6(l), and 6(n) showed the highest fit values against the generated pharmacophore model. Also, QSAR technique was carried out to estimate the proposed PPAR gamma binding affinities and insulin-secreting abilities. The synthesized compounds showed promising estimated activities. In-silico ADMET studies were performed to investigate pharmacokinetics of the synthesized compounds. They showed considerable human intestinal absorption with low BBB penetration.