Background: Considering that inflammation is involved in many degenerative conditions,
some derivatives of tolfenamic acid, naproxen and indomethacin were synthesised and evaluated
biologically. They were found to possess increased anti-inflammatory activity, being more potent than
the parent drugs.
Method: Thus, compound 4, the ester of naproxen with di-tert-butyl-4-(hydroxymethyl)phenol, caused
about 80% reduction of carrageenan-induced rat paw oedema, much higher than that of the starting
drug. The antioxidant structure containing compounds 1-4 could inhibit soybean lipoxygenase, as well
as rat microsomal membrane lipid peroxidation, both effects attributed to the presence of SH or
phenolic groups. The effect of compound 1, the amide of tolfenamic acid with L-cysteine ethyl ester, on
paracetamol-induced oxidative liver injury and on brain oxidative stress caused by ischemia–
reperfusion was examined.
Results: It was found that 1 could protect rat liver from glutathione depletion, being comparable to Nacetylcysteine,
the classical antidote against paracetamol overdose, and restore hepatic function, as
judged by the levels of hepatic enzymes in plasma and the microscopic examination of multiple liver
slices. After cerebral ischemia, 1 reduced caspase-3 by 60% and significantly decreased the number of
apoptotic cells, especially in hippocampus and cerebellum.