Synthesis and biological evaluation of indoline derivatives as CDGSH iron sulfur domain 2 activators

A series of indoline derivatives has been designed, synthesized, and evaluated for their capacity to activate CDGSH iron sulfur domain 2 (Cisd2), a protein implicated in nonalcoholic fatty liver disease (NAFLD), starting with 1-(2,3-dihydro-1H-indol-1-yl)-2-(4,5-dihydro-1,3-thiazol-2-ylsulfanyl)ethan-1-one 3 (EC₅₀ = 569 nM), the hit identified through a two-stage screening strategy followed by substructure searches. Among them, indolines 7 (EC₅₀ = 364 nM) and 10 (EC₅₀ = 315 nM) stood out as the most potent Cisd2 activators and were advanced to in vivo studies. The data conclusively demonstrated that both compounds enhanced Cisd2 expression, yet only 7 effectively halted the development and progression of NAFLD without any detectable toxicity; compound 10 was linked to hepatotoxicity, highlighting its potential risks. Accordingly, the study provided proof of concept that compound 7 is a safe and orally active Cisd2 activator, supporting a therapeutic strategy for the treatment of NAFLD.