Design, Synthesis, and Biological Evaluation of Novel Hydroxyamidine Derivatives as Indoleamine 2,3-Dioxygenase 1 Inhibitors.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-30 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00279

Xiaodan Qiu, Yitong Liu, Xia Zhou, Cong Zhao, Qingguo Meng, Wuli Zhao, Guangzhi Shan

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引用次数: 0

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the conversion of tryptophan into kynurenine and represents a potential target for tumor immunotherapy. In this study, we designed and synthesized a series of N'-hydroxyamidine analogues through pharmacophore fusion and bioisosterism principles. The results indicated that compounds I-1 and I-2 exhibited activity similar to that of Epacadostat in inhibiting recombinant hIDO1 and hIDO1 expression in HeLa cells. Moreover, the compounds not only effectively stimulated T cell proliferation but also inhibited the proliferation of Lewis Lung Carcinoma cells. RNA sequencing analysis indicated that these compounds primarily exert immunotherapeutic effects. Surface plasmon resonance and molecular docking confirmed the interactions between the compounds and IDO1. The physicochemical properties along with pharmacokinetic profiles of both compounds were also predicted, and they were found to possess favorable characteristics. The active compounds developed in this research may serve as valuable references for discovering highly effective IDO1 inhibitors.

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吲哚胺2,3-双加氧酶1抑制剂的设计、合成及生物学评价

吲哚胺2,3-双加氧酶1 （IDO1）是一种催化色氨酸转化为犬尿氨酸的限速酶，是肿瘤免疫治疗的潜在靶点。在本研究中，我们利用药效团融合和生物等构原理设计并合成了一系列N'-羟胺类似物。结果表明，化合物I-1和I-2在HeLa细胞中具有与Epacadostat相似的抑制重组hIDO1和hIDO1表达的活性。此外，化合物不仅能有效刺激T细胞增殖，还能抑制Lewis肺癌细胞的增殖。RNA测序分析表明，这些化合物主要发挥免疫治疗作用。表面等离子体共振和分子对接证实了化合物与IDO1之间的相互作用。预测了两种化合物的理化性质和药代动力学特征，发现它们具有良好的特性。本研究开发的活性化合物可为发现高效的IDO1抑制剂提供有价值的参考。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.