2. Academic Validation
  3. N-Salicyloyl Tryptamine Derivatives as Potent Neuroinflammation Inhibitors by Constraining Microglia Activation via a STAT3 Pathway

N-Salicyloyl Tryptamine Derivatives as Potent Neuroinflammation Inhibitors by Constraining Microglia Activation via a STAT3 Pathway

  • ACS Chem Neurosci. 2024 Jul 3;15(13):2484-2503. doi: 10.1021/acschemneuro.4c00060.
Yuting Zhao 1,  Yan Peng 2,  Xiuzhen Wei 2,  Genping Wu 1,  Bo Li 2,  Xuelin Li 2 3,  Lin Long 2,  Jing Zeng 2,  Wei Luo 2,  Ying Tian 1,  Zhen Wang 2 3 4 5,  Xue Peng 2
Affiliations

Affiliations

  • 1 The Affiliated Nanhua Hospital, Department of Clinical Laboratory, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 2 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 3 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 4 National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.
  • 5 MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan 410000, China.
PMID: 38865609 DOI: 10.1021/acschemneuro.4c00060
Abstract

Neuroinflammation is an important factor that exacerbates neuronal death and abnormal synaptic function in neurodegenerative diseases (NDDs). Due to the complex pathogenesis and the presence of blood-brain barrier (BBB), no effective clinical drugs are currently available. Previous results showed that N-salicyloyl tryptamine derivatives had the potential to constrain the neuroinflammatory process. In this study, 30 new N-salicyloyl tryptamine derivatives were designed and synthesized to investigate a structure-activity relationship (SAR) for the indole ring of tryptamine in order to enhance their antineuroinflammatory effects. Among them, both in vitro and in vivo compound 18 exerted the best antineuroinflammatory effects by suppressing the activation of microglia, which is the culprit of neuroinflammation. The underlying mechanism of its antineuroinflammatory effect may be related to the inhibition of transcription, expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) that subsequently regulated downstream cyclooxygenase-2 (COX-2) expression and activity. With its excellent BBB permeability and pharmacokinetic properties, compound 18 exhibited significant neuroprotective effects in the hippocampal region of lipopolysaccharides (LPS)-induced mice than former N-salicyloyl tryptamine derivative L7. In conclusion, compound 18 has provided a new approach for the development of highly effective antineuroinflammatory therapeutic drugs targeting microglia activation.

Keywords

N-salicyloyloyl tryptamine derivatives; STAT3; blood–brain barrier; microglia activation; neurodegenerative diseases; neuroinflammation.

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