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

• Published in: Bioorganic & medicinal chemistry 2017-02, Vol.25 (4), p.1496-1513
• Main Authors: Ibrahim, Mohammed K., Eissa, Ibrahim H., Abdallah, Abdallah E., Metwaly, Ahmed M., Radwan, M.M., ElSohly, M.A.
• Format: Article
• Language: English
• Subjects: Animals; Anti-hyperglycemic; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Docking; Dose-Response Relationship, Drug; Drug Design; Hyperglycemia - chemically induced; Hyperglycemia - drug therapy; Male; Models, Molecular; Molecular Structure; Pharmacophore; PPAR gamma - agonists; PPARγ; Quinoxaline; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Rats; Rats, Wistar; Streptozocin; Structure-Activity Relationship; Sulfonylthiourea; Sulfonylurea; Sulfonylurea Receptors - agonists
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.01.015

[Display omitted] •Eighteen compounds of novel quinoxaline derivatives were designed and synthesized.•Molecular docking and pharmacophore studies were carried out.•In vivo anti-hyperglycemic activity, in vitro PPARγ binding affinity and insulin-secreting ability were carried out.•Some of the synthesized compounds showed promising anti-hyperglycemic activity. 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 15a, 15e, 19b and 24a 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 (15a, 15b, 15d and 15e) significantly bound to PPARγ with IC50 values of 0.482, 0.491, 0.350 and 0.369μM, respectively. Moreover, Compounds 15a and 15b 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.