Analysis on benzothiazole necroptosis inhibitors with chiral substitutions in the solvent-accessible region of RIP kinase domain

•The E0 region of RIPK1/RIPK3 kinase domain is related to the potency and selectivity of inhibitors.•The linker residues, β1-strand, and αJ-chain around E0 region of RIPK1 and RIPK3 are different.•A series of benzothiazole inhibitors with chiral substitutions in the linker region were developed.•The results showed a 2-to 6-fold increase in anti-necroptotic activity for these chiral compounds.•Our found will guide further rational design of chiral necroptosis inhibitors.