Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors

Xiaojun Yang; Shi Cai; Xueting Liu; Pan Chen; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.bmc.2019.03.005

Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1605-1618. doi: 10.1016/j.bmc.2019.03.005. Epub 2019 Mar 5.

Authors

Xiaojun Yang¹, Shi Cai¹, Xueting Liu², Pan Chen², Jinpei Zhou³, Huibin Zhang⁴

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China. Electronic address: jpzhou668@163.com.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: zhanghb80@cpu.edu.cn.

PMID: 30858027
DOI: 10.1016/j.bmc.2019.03.005

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC₅₀ = 4.0 nM, THP-1 cellular IC₅₀ = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety. These results indicate that compound 19a is a potential IDO1 inhibitor for further investigation.

Keywords: HeLa assay; IDO1 inhibitor; Immunotherapy; THP-1 assay.

Publication types

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

MeSH terms

Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Furans / chemistry*
Furans / metabolism
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Inhibitory Concentration 50
Molecular Docking Simulation
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Furans
Indoleamine-Pyrrole 2,3,-Dioxygenase
2,5-dimethylfuran