title: Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of novel quinoxaline derivatives as potential PPARγ and SUR agonists.
abstract: 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, 19band 24aexhibited 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, 15dand 15e) significantly bound to PPARγ with IC50values of 0.482, 0.491, 0.350 and 0.369μM, respectively. Moreover, Compounds 15aand 15bhave demonstrated induction of insulin-secretion with EC50values 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.
authors.affiliation: Pharmaceutical Chemistry Departments, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Ibrahim
authors.affiliation: Pharmaceutical Chemistry Departments, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: Ibrahimeissa@azhar.edu.eg.
authors.forename: Ibrahim H
authors.initials: IH
authors.lastname: Eissa
authors.affiliation: Pharmaceutical Chemistry Departments, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Abdallah E
authors.initials: AE
authors.lastname: Abdallah
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy (Boys), University of Al-Azhar, Cairo 11884, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Metwaly
authors.affiliation: National Center for Natural Products Research, University of Mississippi University, MS 38677, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Radwan
authors.affiliation: National Center for Natural Products Research, University of Mississippi University, MS 38677, USA. Electronic address: Melsohly@olemiss.edu.
authors.forename: M A
authors.initials: MA
authors.lastname: ElSohly
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors / Q000819:agonists*
chemical_list: D000959:Antihypertensive Agents; D047495:PPAR gamma; D011810:Quinoxalines; D064233:Sulfonylurea Receptors; D013311:Streptozocin
keywords: Anti-hyperglycemic; Docking; PPARγ; Pharmacophore; Quinoxaline; Sulfonylthiourea; Sulfonylurea