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

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.