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.

Xiaojun Yang ¹, Shi Cai ¹, Xueting Liu ², Pan Chen ², Jinpei Zhou ³, Huibin Zhang ⁴

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.

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