New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation

Yingying Zheng; Li Lu; Mengyue Li; DeHua Xu; LaiShun Zhang; Zhuang Xiong; Yubo Zhou; Jia Li; Xuetao Xu; Kun Zhang; Lei Xu

doi:10.1016/j.bioorg.2023.106985

New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation

Bioorg Chem. 2024 Feb:143:106985. doi: 10.1016/j.bioorg.2023.106985. Epub 2023 Nov 23.

Authors

Yingying Zheng¹, Li Lu¹, Mengyue Li¹, DeHua Xu², LaiShun Zhang³, Zhuang Xiong¹, Yubo Zhou⁴, Jia Li⁴, Xuetao Xu⁵, Kun Zhang⁶, Lei Xu⁷

Affiliations

¹ Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, PR China.
² Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China; School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, PR China.
³ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China; School of Pharmacy, Zunyi Medical University, Zunyi 563006, PR China.
⁴ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁵ Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, PR China. Electronic address: wyuchemxxt@126.com.
⁶ Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, PR China. Electronic address: Kzhang@gdut.edu.cn.
⁷ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China. Electronic address: 0024xl@zidd.ac.cn.

PMID: 38007892
DOI: 10.1016/j.bioorg.2023.106985

Abstract

A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 ∼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC₅₀ values of 1.40 ± 0.04 ∼ 16.83 ± 0.54 μM comparing to that of positive control lithocholic acid (IC₅₀: 9.62 ± 0.14 μM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC₅₀ value of 1.40 ± 0.04 μM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced insulin resistance by increasing the phosphorylation of IRSI and AKT. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.

Keywords: Chromone; Inhibitors; Protein tyrosine phosphatase 1B; Thiazolidine-2,4-dione.

MeSH terms

Drug Design
Enzyme Inhibitors* / chemistry
Molecular Docking Simulation
Palmitic Acid / pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 1*
Structure-Activity Relationship
Thiazolidinediones*
Thiazolidines

Substances

thiazolidine-2,4-dione
Thiazolidines
Enzyme Inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Palmitic Acid
Thiazolidinediones