(E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety as potential immunosuppressive agents: Design, synthesis, molecular docking and biological evaluation

Xian-Hai Lv; Qing-Shan Li; Zi-Li Ren; Ming-Jie Chu; Jian Sun; Xin Zhang; Man Xing; Hai-Liang Zhu; Hai-Qun Cao

doi:10.1016/j.ejmech.2015.12.020

(E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety as potential immunosuppressive agents: Design, synthesis, molecular docking and biological evaluation

Eur J Med Chem. 2016 Jan 27:108:586-593. doi: 10.1016/j.ejmech.2015.12.020. Epub 2015 Dec 15.

Authors

Xian-Hai Lv¹, Qing-Shan Li², Zi-Li Ren¹, Ming-Jie Chu¹, Jian Sun³, Xin Zhang³, Man Xing³, Hai-Liang Zhu³, Hai-Qun Cao⁴

Affiliations

¹ College of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China.
² School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
⁴ College of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China. Electronic address: haiquncao@163.com.

PMID: 26720154
DOI: 10.1016/j.ejmech.2015.12.020

Abstract

A series of novel (E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety were firstly synthesized and their immunosuppressive activities were evaluated. Among all the compounds, 4n exhibited the most potent inhibitory activity (IC50 = 1.18 μM for lymph node cells and IC50 = 0.28 μM for PI3Kγ), which was comparable to that of positive control. Moreover, selected compounds were tested for their inhibitory activities against IL-6 released in ConA-simulated mouse lymph node cells, 4n exhibited the most potent inhibitory ability. Furthermore, in order to study the preliminary mechanism of the compounds with potent inhibitory activity, the RT-PCR experiment was performed to assay the effect of selected compounds on mRNA expression of IL-6. Among them, compound 4n strongly inhibited the expression of IL-6 mRNA.

Keywords: Immunosuppressant; Molecular docking; Oxime ethers; PI3Kγ; Pyrazole.

Publication types

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

MeSH terms

Animals
Class Ib Phosphatidylinositol 3-Kinase / metabolism
Drug Design*
Gene Expression Regulation / drug effects
Immunosuppressive Agents / chemical synthesis
Immunosuppressive Agents / chemistry
Immunosuppressive Agents / pharmacology*
Interleukin-6 / genetics
Interleukin-6 / metabolism
Lymph Nodes / cytology
Lymph Nodes / drug effects
Lymph Nodes / immunology
Lymph Nodes / metabolism
Mice
Molecular Docking Simulation*
Molecular Structure
Oximes / chemistry
Oximes / pharmacology*
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Structure-Activity Relationship

Substances

(E)-1,3-diphenyl-1H-pyrazole
Immunosuppressive Agents
Interleukin-6
Oximes
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyrazoles
RNA, Messenger
Class Ib Phosphatidylinositol 3-Kinase
Pik3cg protein, mouse