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J Med Chem. 2018 May 10;61(9):4004-4019. doi: 10.1021/acs.jmedchem.8b00001. Epub 2018 Apr 27.

Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents.

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Department of Chemistry , Bar Ilan University , Ramat Gan 5290002 , Israel.
Institute of Drug Research , The Hebrew University of Jerusalem , Jerusalem 9112102 , Israel.


We describe the preparation and evaluation of novel indoline derivatives with potent antioxidant and anti-inflammatory activities for the treatment of pathological conditions associated with chronic inflammation. The indolines are substituted at position 1 with chains carrying amino, ester, amide, or alcohol groups, and some have additional substituents, Cl, MeO, Me, F, HO, or BnO, on the benzo ring. Concentrations of 1 pM to 1 nM of several compounds protected RAW264.7 macrophages against H2O2 induced cytotoxicity and LPS induced elevation of NO, TNF-α, and IL-6. Several derivatives had anti-inflammatory activity at 1/100th of the concentration of unsubstituted indoline. Four compounds with ester, amine, amide, or alcohol side chains injected subcutaneously in mice at a dose of 1 μmol/kg or less, like dexamethasone (5.6 μmol/kg) prevented LPS-induced cytokine elevation in the brain and peripheral tissues. Subcutaneous injection of 100 μmol/kg of these compounds caused no noticeable adverse effects in mice during 3 days of observation.

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