2. Academic Validation
  3. Design, synthesis, and SAR study of novel 4,5-dihydropyrazole-Thiazole derivatives with anti-inflammatory activities for the treatment of sepsis

Design, synthesis, and SAR study of novel 4,5-dihydropyrazole-Thiazole derivatives with anti-inflammatory activities for the treatment of sepsis

  • Eur J Med Chem. 2021 Dec 5:225:113743. doi: 10.1016/j.ejmech.2021.113743.
Zhen Zhang 1,  Peichang Cao 1,  Mengyuan Fang 1,  Tingfeng Zou 1,  Jihong Han 1,  Yajun Duan 1,  Huajian Xu 1,  Xiaoxiao Yang 2,  Qing-Shan Li 3
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 2 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: [email protected].
  • 3 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: [email protected].
PMID: 34403978 DOI: 10.1016/j.ejmech.2021.113743
Abstract

Systemic inflammatory response syndrome is a major feature of sepsis which is one of the major causes of death worldwide. It has been reported that 3,5-diaryl-4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazole moiety into dihydropyrazole skeleton to design and synthesize a novel series of 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole derivatives, and evaluated their anti-inflammatory activities for sepsis treatment. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in LPS-induced RAW264.7 cells, and the optimal compound E26 exhibited more potent anti-inflammatory activity than the positive control treatment indomethacin and dexamethasone. In further mechanism study, our results showed that compound E26 significantly suppressed the production of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), NO and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking MAPKs signaling pathway. In addition, in vivo administration of compound E26 resulted in a significant improvement of LPS-induced sepsis in C57BL/6J mice, with reducing toxicity in multiple organs. Taken together, this study demonstrated the compound E26 could be a promising agent for the treatment of sepsis.

Keywords

Anti-inflammatory agents; Dihydropyrazole; SAR; Sepsis; Thiazole.

Figures
Products