title: Synthesis and structure-activity relationship of non-phosphorus-based fructose-1,6-bisphosphatase inhibitors: 2,5-Diphenyl-1,3,4-oxadiazoles.
abstract: With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure-activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China.
authors.forename: Ben-Ren
authors.initials: BR
authors.lastname: Liao
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China; Chemistry and Chemical Engineering, Nantong University, Jiangsu 226019, China.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: He
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Gao
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chang
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China. Electronic address: jyli@mail.shcnc.ac.cn.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Li
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China. Electronic address: jli@mail.shcnc.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China. Electronic address: fyang@chem.ecnu.edu.cn.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D006597:Fructose-Bisphosphatase; D005947:Glucose
keywords: 2,5-Diphenyl-1,3,4-oxadiazoles; Antidiabetic; Diabetes; Fructose-1,6-bisphosphatase (FBPase); Inhibitor