Design, synthesis and biological evaluation of 7-nitro-1H-indole-2-carboxylic acid derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase

Jianbo Bie; Shuainan Liu; Jie Zhou; Bailing Xu; Zhufang Shen

doi:10.1016/j.bmc.2014.01.047

Design, synthesis and biological evaluation of 7-nitro-1H-indole-2-carboxylic acid derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase

Bioorg Med Chem. 2014 Mar 15;22(6):1850-62. doi: 10.1016/j.bmc.2014.01.047. Epub 2014 Feb 2.

Authors

Jianbo Bie¹, Shuainan Liu¹, Jie Zhou¹, Bailing Xu², Zhufang Shen³

Affiliations

¹ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
² Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: xubl@imm.ac.cn.
³ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: shenzhf@imm.ac.cn.

PMID: 24530031
DOI: 10.1016/j.bmc.2014.01.047

Abstract

A series of novel indole derivatives was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). Extensive structure-activity relationships were conducted and led to a potent FBPase inhibitor 3.9 with an IC₅₀ of 0.99 μM. The binding mode of this series of indoles was predicted using CDOCKER algorithm. The results of this research will shed light on the further design and optimization of novel small molecules as FBPase inhibitors.

Keywords: 6-Bisphosphatase inhibitor; Allosteric inhibitor; Diabetes; Fructose-1; Indole.

Publication types

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

MeSH terms

Allosteric Regulation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fructose-Bisphosphatase / antagonists & inhibitors*
Fructose-Bisphosphatase / metabolism
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

7-nitro-1H-indole-2-carboxylic acid
Enzyme Inhibitors
Indoles
Recombinant Proteins
Fructose-Bisphosphatase