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

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.

• Authors: Zhen Zhang, Peichang Cao, Mengyuan Fang, Tingfeng Zou, Jihong Han, Yajun Duan, Huajian Xu, Xiaoxiao Yang, Qing-Shan Li
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 225 Pg. 113743 (Dec 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 34403978 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cytokines
• Lipopolysaccharides
• Pyrazoles
• Thiazoles
• Nitric Oxide

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Cytokines (antagonists & inhibitors, biosynthesis)
• Dose-Response Relationship, Drug
• Drug Design
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Nitric Oxide (antagonists & inhibitors, biosynthesis)
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• RAW 264.7 Cells
• Sepsis (drug therapy, metabolism)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)