Endoplasmic reticulum (ER) stress‐induced Pancreatic β‐cell dysfunction and death plays important roles in the development of diabetes. The 1,2,3‐triazole derivative 1 is one of only a few structures that have thus far been identified that protect β cells against ER stress, but it is limited for its narrow activity range. In this study, we designed and synthesized a series of hydroxybenzamide (HBA) derivatives in which the triazole pharmacophore was substituted with an amide linker. Structure–activity relationship studies identified WO3i (3‐hydroxy‐N‐(4‐[trifluoromethyl]benzyl)benzamide) that possesses β‐cell protective activity against ER stress at a 100% maximal activity with EC50 at 0.19 μM). We showed that WO3i suppresses the expression of CHOP, a key mediator of ER stress‐induced apoptosis, and the activation of apoptotic genes. Mechanistically, we further showed that WO3i suppresses the ER stress‐induced activation of all three pathways of unfolded protein response—ATF6, IRE1α, and PERK. Identification of this novel β‐cell‐protective scaffold thus provides a new promising modality for the potential for drug development for the treatment of diabetes.
