Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of novel quinoxaline derivatives as potential...

In our effort to develop potent anti-hyperglycemic agents with potential agonistic activities toward PPARγ and SUR, three novel series of quinoxaline derivatives bearing sulfonylurea or sulfonylthiourea moieties with different linkers were designed and synthesized. Some of the newly synthesized compounds were evaluated in vivo for their anti-hyperglycemic activities in STZ-induced hyperglycemic rats. Compounds 15_a, 15_e, 19_b and 24_a exhibited the highest anti-hyperglycemic activities with % reduction in blood glucose level of (50.58, 43.84, 45.10 and 49.62, respectively). Additionally, eight compounds revealed potent anti-hyperglycemic activities were further evaluated in vitro for their PPARγ binding affinity and insulin-secreting ability as potential mechanisms for anti-hyperglycemic activity. Four compounds (15_a, 15_b, 15_d and 15_e) significantly bound to PPARγ with IC₅₀ values of 0.482, 0.491, 0.350 and 0.369μM, respectively. Moreover, Compounds 15_a and 15_b have demonstrated induction of insulin-secretion with EC₅₀ values of 0.92 and 0.98μM, 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.