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

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.