Design and synthesis of new potent PTP1B inhibitors with the skeleton of 2-substituted imino-3-substituted-5-heteroarylidene-1,3-thiazolidine-4-one: Part I

Ge Meng; Meilin Zheng; Mei Wang; Jing Tong; Weijuan Ge; Jiehe Zhang; Aqun Zheng; Jingya Li; Lixin Gao; Jia Li

doi:10.1016/j.ejmech.2016.05.060

Design and synthesis of new potent PTP1B inhibitors with the skeleton of 2-substituted imino-3-substituted-5-heteroarylidene-1,3-thiazolidine-4-one: Part I

Eur J Med Chem. 2016 Oct 21:122:756-769. doi: 10.1016/j.ejmech.2016.05.060. Epub 2016 May 28.

Authors

Ge Meng¹, Meilin Zheng², Mei Wang², Jing Tong², Weijuan Ge², Jiehe Zhang², Aqun Zheng³, Jingya Li⁴, Lixin Gao⁴, Jia Li⁵

Affiliations

¹ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China. Electronic address: mengge@mail.xjtu.edu.cn.
² School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China.
³ School of Science, Xi'an Jiaotong University, No. 28, Xianning West Road, Xi'an, Shaanxi, 710049, PR China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: jli@mail.shcnc.ac.cn.

PMID: 27526040
DOI: 10.1016/j.ejmech.2016.05.060

Abstract

A new series of 2-substituted imino-3-substituted-5- heteroarylidene-1,3-thiazolidine-4-ones as the potent bidentate PTP1B inhibitors were designed and synthesized in this paper. All of the new compounds were characterized and identified by spectra analysis. The biological screening test against PTP1B showed that some of these compounds have the positive inhibitory activity against PTP1B. The activity of the compounds with 5-substituted pyrrole on 5-postion of 1,3-thiazolidine-4-one are more potent than that of those compounds with 5-substituted pyridine group. Compound 14b, 14h and 14i showed IC50 values of 8.66 μM, 6.83 μM and 6.09 μM against PTP1B, respectively. Docking analysis of these active compounds with PTP1B showed the possible interaction modes of these biheterocyclic compounds with the active sites of PTP1B. The inhibition tests against oncogenetic CDC25B were also conducted on this set of compounds to evaluate the selectivity and possible anti-neoplastic activity. Compound 14b also showed the lowest IC50 of 1.66 μM against CDC25B among all the possible inhibitors, including 14g, 14h, 14i and 15c. Some pharmacological parameters including VolSurf, steric and electric descriptors of all the compounds were calculated to give some hints about the relative relationship with the biological activity. The result of this study might give some light on designing the possible anti-cancer drugs targeting at phosphatases. The most active compound 14i might be used as the lead compound for further structure modification of the new low molecular weight PTP1B inhibitors with the N-containing heterocyclic skeleton.

Keywords: 1,3-Thiazolidine-4-one; Dock; PTP1B; Pyridine; Pyrrole; SAR.

MeSH terms

Chemistry Techniques, Synthetic
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Protein Conformation
Protein Structure, Secondary
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Structure-Activity Relationship
Thiazolidines / chemical synthesis*
Thiazolidines / chemistry
Thiazolidines / metabolism
Thiazolidines / pharmacology*
cdc25 Phosphatases / antagonists & inhibitors

Substances

Enzyme Inhibitors
Thiazolidines
PTPN1 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1
cdc25 Phosphatases