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

  • Bioorg Chem. 2024 Nov:152:107740. doi: 10.1016/j.bioorg.2024.107740.
Ting Wang  1 ,  Xiufeng Liao  1 ,  Xiaodi Zhao  2 ,  Kai Chen  3 ,  Yangzhonghui Chen  1 ,  Hui Wen  1 ,  Dali Yin  1 ,  Yuchen Wang  4 ,  Bin Lin  5 ,  Sen Zhang  6 ,  Huaqing Cui  7
Affiliations
  • 1. Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, China.
  • 2. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, China.
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, China. Electronic address: [email protected].
  • 5. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, China. Electronic address: [email protected].
  • 7. Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, China. Electronic address: [email protected].
PMID: 39217780 DOI: 10.1016/j.bioorg.2024.107740
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.

Keywords
2-Benzylsulfinyl-benzoxazole; Indoleamine 2,3-dioxygenase 1; Inflammation; Transition state inhibitor; Tryptophan metabolism.
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