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ORIGINAL RESEARCH article

Front. Pharmacol.

Sec. Neuropharmacology

Volume 16 - 2025 | doi: 10.3389/fphar.2025.1574007

Rational Design of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Featuring 1,2,3-Triazole Derivatives with Enhanced Anti-inflammatory and Analgesic Efficacy

Provisionally accepted
Xixi  HouXixi Hou1*Qing-Ying  LiuQing-Ying Liu2*Yueliang  WangYueliang Wang2Mingyue  TianMingyue Tian2Baoyu  HeBaoyu He3Jingjing  GuoJingjing Guo3Jianxue  YangJianxue Yang4*
  • 1The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
  • 2Zhengzhou University, Zhengzhou, Henan Province, China
  • 3Macao Polytechnic University, Macau, Macao, SAR China
  • 4Henan University of Science and Technology, Luoyang, Henan Province, China

The final, formatted version of the article will be published soon.

This study applied a target-based drug design approach focused on the IDO1 enzyme, which features a heme active site. By introducing a 1,2,3-triazole moiety capable of coordinating with the ferrous ion in heme, a series of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed. Enzyme assays demonstrated that these compounds generally inhibited IDO1 activity, with Compound 14e showing the most potent effect, achieving an IC50 value of 3.63 μM. Molecular docking studies indicated that the 1,2,3-triazole ring in Compound 14e is positioned directly above the heme, forming a coordination bond with the ferrous ion. Additionally, it engages in π-π interactions with Phe263, while the amide group of the 2H-benzo[b][1,4]oxazin-3(4H)-one scaffold forms hydrogen bonds with Lys238. In vivo experiments in mice showed that Compound 14e significantly reduced CFA-induced upregulation of Iba1 in the spinal dorsal horn and alleviated mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain. Moreover, treatment with Compound 14e led to a significant reduction in the levels of pro-inflammatory cytokines TNF-α and IL-1β in CFA-treated mice. Importantly, Compound 14e demonstrated a favorable safety profile, with no observed toxicity in major organs, highlighting its potential as a promising anti-inflammatory and analgesic agent targeting IDO1.

Keywords: 1,2,3-Triazoles, IDO1 inhibitor, 2H-benzo[b][1,4]oxazin-3(4H)-one, anti-inflammatory, analgesic

Received: 10 Feb 2025; Accepted: 01 Sep 2025.

Copyright: © 2025 Hou, Liu, Wang, Tian, He, Guo and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Xixi Hou, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
Qing-Ying Liu, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
Jianxue Yang, Henan University of Science and Technology, Luoyang, 471003, Henan Province, China

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