Synthesis and structure-activity relationship of non-phosphorus-based fructose-1,6-bisphosphatase inhibitors: 2,5-Diphenyl-1,3,4-oxadiazoles

Ben-Ren Liao; Hai-Bing He; Ling-Ling Yang; Li-Xin Gao; Liang Chang; Jie Tang; Jing-Ya Li; Jia Li; Fan Yang

doi:10.1016/j.ejmech.2014.06.011

Synthesis and structure-activity relationship of non-phosphorus-based fructose-1,6-bisphosphatase inhibitors: 2,5-Diphenyl-1,3,4-oxadiazoles

Eur J Med Chem. 2014 Aug 18:83:15-25. doi: 10.1016/j.ejmech.2014.06.011. Epub 2014 Jun 10.

Authors

Ben-Ren Liao¹, Hai-Bing He², Ling-Ling Yang³, Li-Xin Gao³, Liang Chang¹, Jie Tang¹, Jing-Ya Li⁴, Jia Li⁵, Fan Yang⁶

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China.
² 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.
³ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.
⁴ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China. Electronic address: jyli@mail.shcnc.ac.cn.
⁵ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China. Electronic address: jli@mail.shcnc.ac.cn.
⁶ 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.

PMID: 24946215
DOI: 10.1016/j.ejmech.2014.06.011

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.

Keywords: 2,5-Diphenyl-1,3,4-oxadiazoles; Antidiabetic; Diabetes; Fructose-1,6-bisphosphatase (FBPase); Inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chemistry Techniques, Synthetic
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Fructose-Bisphosphatase / antagonists & inhibitors*
Fructose-Bisphosphatase / chemistry
Fructose-Bisphosphatase / metabolism
Glucose / metabolism
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Kinetics
Molecular Docking Simulation
Oxadiazoles / chemical synthesis*
Oxadiazoles / chemistry
Oxadiazoles / metabolism
Oxadiazoles / pharmacology*
Protein Conformation
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Oxadiazoles
Fructose-Bisphosphatase
Glucose