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

Chun-Hsu Yao; Lee-Ya Wang; Zhao-Qing Shen; Yu-Wen Huang; Chi-Hui Tsai; Jen-Shin Song; Chi-Han Chen; Yu-Chun Chen; Ting-Fen Tsai; Jinq-Chyi Lee

doi:10.1016/j.bmc.2025.118281

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

Bioorg Med Chem. 2025 Jun 8:128:118281. doi: 10.1016/j.bmc.2025.118281. Online ahead of print.

Authors

Affiliations

¹ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan.
² Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
³ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. Electronic address: tftsai@nycu.edu.tw.
⁴ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan. Electronic address: jinqchyi@nhri.edu.tw.

PMID: 40527104
DOI: 10.1016/j.bmc.2025.118281

Abstract

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.

Keywords: Cisd2 activator; Indoline; Nonalcoholic fatty liver disease.