Discovery of chalcone analogues as novel NLRP3 inflammasome inhibitors with potent anti-inflammation activities.

Abstract

NLRP3 inflammasome activation plays a critical role in inflammation and its related disorders. Herein we report a hit-to-lead effort resulting in the discovery of a novel and potent class of NLRP3 inflammasome inhibitors. Among these, the most potent lead 40 exhibited improved inhibitory potency and almost no toxicity. Further mechanistic study indicated that compound 40 inhibited the NLRP3 inflammasome activation via suppressing ROS production. More importantly, treatment with 40 showed remarkable therapeutic effects on LPS-induced sepsis and DSS-induced colitis. This study encourages further development of more potent inhibitors based on this chemical scaffold and provides a chemical tool to identify its cellular binding target.

• Authors: Cheng Zhang, Hu Yue, Ping Sun, Lei Hua, Shuli Liang, Yitao Ou, Dan Wu, Xinyi Wu, Hao Chen, Ying Hao, Wenhui Hu, Zhongjin Yang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 219 Pg. 113417 (Jul 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33845232 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Chalcones
• Inflammasomes
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species

Topics

• Animals
• Anti-Inflammatory Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Cell Line
• Chalcones (chemistry, metabolism, pharmacology, therapeutic use)
• Colitis (chemically induced, drug therapy)
• Disease Models, Animal
• Drug Design
• Female
• Inflammasomes (drug effects, metabolism)
• Lipopolysaccharides (toxicity)
• Macrophages (cytology, drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, metabolism)
• Pyroptosis (drug effects)
• Reactive Oxygen Species (metabolism)
• Sepsis (drug therapy, etiology)
• Structure-Activity Relationship