2. Academic Validation
  3. Design, synthesis, and anti-necroptotic activity of novel Phenylbenzothiazole receptor-interacting protein kinase 1 (RIPK1) inhibitors

Design, synthesis, and anti-necroptotic activity of novel Phenylbenzothiazole receptor-interacting protein kinase 1 (RIPK1) inhibitors

  • Bioorg Med Chem Lett. 2026 Mar 3:136:130613. doi: 10.1016/j.bmcl.2026.130613.
Jing Tao 1,  Yuelun Xu 2,  Zijun Chen 1,  Yang Liu 1,  Xiong Zuo 1,  Tao Yuan 3,  Houzong Yao 4
Affiliations

Affiliations

  • 1 Jiangxi Provincial Key Laboratory of Natural and Biomimetic Drugs Research, College of Pharmacy, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China.
  • 2 Institute of Flow Chemistry and Engineering, School of Chemistry and Materials, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China.
  • 3 Jiangxi Provincial Key Laboratory of Natural and Biomimetic Drugs Research, College of Pharmacy, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China. Electronic address: tyuan@jxnu.edu.cn.
  • 4 Jiangxi Provincial Key Laboratory of Natural and Biomimetic Drugs Research, College of Pharmacy, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China; Institute of Flow Chemistry and Engineering, School of Chemistry and Materials, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China. Electronic address: yaohz@jxnu.edu.cn.
PMID: 41786053 DOI: 10.1016/j.bmcl.2026.130613
Abstract

Receptor-interacting protein kinase 1 (RIPK1) is a central regulator of Necroptosis and a promising therapeutic target for inflammatory and degenerative diseases. Guided by computer-aided drug design (CADD) and structure-based optimizations, we developed a series of phenylbenzothiazole derivatives to enhance RIPK1 inhibition. A total of 36 analogs were efficiently synthesized and fully characterized, incorporating systematic modifications at the R(Degterev et al., 20051), R(Vanlangenakker et al., 20122), and R3 positions. Their anti-necroptotic activity was evaluated in HT-29 cells under TNF-induced Necroptosis. Several compounds (27, 43, 44, and 51) demonstrated significantly improved potency over the lead molecule 18. SAR analysis revealed that CF3 or OCF3 at R(Degterev et al., 20051), F or H at R(Vanlangenakker et al., 20122), and 3-oxocyclobutyl or 3-oxocyclopentyl groups at R3 greatly enhanced activity, indicating more favorable interactions within the RIPK1 binding pocket. These findings identify new phenylbenzothiazole-based inhibitors with promising anti-necroptotic effects and highlight key structural features for future optimization.

Keywords

CADD; Necroptosis; Phenylbenzothiazole derivatives; RIPK1 inhibitors; Structure-based optimization.

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