Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency

A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC50 3.4 mu M and 2.8 mu M), several times more potent than the reference Trolox (IC50 25 mu M). Most of the compounds decreased carrageenan-induced rat paw edema (37-67% at 150 mu mol/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC50 13 mu M). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 mu mol/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions.

Automated summary

A series of L-serine amides of antioxidant acids were synthesized, with Trolox derivatives containing ibuprofen and ketoprofen showing the most potent inhibition of lipid peroxidation. These compounds also exhibited moderate inhibition of soybean lipoxygenase and significant decrease in lipidemic indices in Triton-induced hyperlipidemic rats, similar to the effects of simvastatin. The designed compounds may have potential therapeutic applications for inflammatory and degenerative conditions.