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Discovery of N-phenyl-1-(phenylsulfonamido)cyclopropane-1-carboxamide analogs as NLRP3 inflammasome inhibitors

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Abstract

Two series of novel NLRP3 inflammasome inhibitors are designed, synthesized, and evaluated in an effort to develop diversified analogs based on the N-(phenylcarbamoyl)benzenesulfonamide scaffold. SAR studies reveal that the sulfonylurea linker can tolerate chemical modifications with either simply changing over the position of carbonyl and sulfonyl group or structurally flexibly inserting a cyclopropyl group, leading to identification of several more potent and diversified NLRP3 antagonists (e.g., 9) with low nanomolar inhibitory activities. Further studies indicate that these two series of compounds with low cytotoxicity exhibited weak effects on the generation of NO and TNF-a. The findings may serve as good starting points for the development of more potent NLRP3 inflammasome inhibitors as valuable pharmacological probes or potential drug candidates.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31970909, 81703330, and 81372688), the Natural Science Foundation of Jiangsu Province (BK20170347), the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD), Suzhou Municipal Science and Technology Bureau (SYS2020092), and the Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003).

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  1. These authors contributed equally: Wanwan Li, Zhongqiang Cao

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  1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China

    Wanwan Li, Zhongqiang Cao, Junjie Cheng, Feiyu Chen, Shuai Li, Yiwei Huang, Long Tai Zheng & Na Ye

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Li, W., Cao, Z., Cheng, J. et al. Discovery of N-phenyl-1-(phenylsulfonamido)cyclopropane-1-carboxamide analogs as NLRP3 inflammasome inhibitors. Med Chem Res 30, 1294–1308 (2021). https://doi.org/10.1007/s00044-021-02740-7

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