Rational design of 2-benzylsulfinyl-benzoxazoles as potent and selective indoleamine 2,3-dioxygenase 1 inhibitors to combat inflammation

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-08-22 DOI:10.1016/j.bioorg.2024.107740

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Abstract

Mimicking the transition state of tryptophan (Trp) and O₂ in the enzymatic reaction is an effective approach to design indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC₅₀ of 82–91 nM, and exhibited selectivity between IDO1 and tryptophan 2,3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.

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合理设计 2-苄基亚磺酰基苯并噁唑作为强效选择性吲哚胺 2,3- 二氧合酶 1 抑制剂以抗击炎症

模拟色氨酸（Trp）和 O2 在酶促反应中的过渡态是设计吲哚胺 2,3-二氧合酶 1（IDO1）抑制剂的有效方法。在这项研究中，我们首先建立了一个小型的 2-取代苯并融合五元杂环化合物库，发现了具有有趣的 IDO1 抑制活性的 2-亚磺酰基苯并恶唑。接下来，IDO1 的抑制活性逐渐提高。几种苯并恶唑对 IDO1 具有很强的抑制活性，其 IC50 值为 82-91 nM，并且在 IDO1 和色氨酸 2,3-二氧合酶（TDO2）之间具有选择性。酶结合研究表明，苯并恶唑是可逆的 II 型 IDO1 抑制剂，模型研究表明苯并恶唑中亚砜的氧原子与血红素基团的铁原子相互作用，模拟了 Fe-O-O-Trp 复合物的过渡态。特别是 10b 能有效抑制脂多糖（LPS）刺激 RAW264.7 细胞产生 NO，对小鼠巴豆油诱导的急性炎症模型耳水肿也有良好的抗炎作用。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.

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