Novel polyfunctional esters of ibuprofen and ketoprofen with hypolipidemic, lipoxygenase inhibitory and enhanced anti-inflammatory activity

A series of ibuprofen and ketoprofen esters were designed and synthesised, incorporating an antioxidant moiety, such as quercetin and salicylic alcohol, as well as anti-inflammatory or neuroprotective components. They showed greatly increased activity against carrageenan-induced inflammation, compared with the parent drugs. They could also reduce significantly total cholesterol and triglyceride levels in the plasma of Triton-induced hyperilipidemic rats. Most of them inhibited rat microsomal membrane lipid peroxidation. They also acquire lipoxygenase inhibitory activity and at least two of them could inhibit cyclooxygenases-1/2. 2-Hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl 2-(4-isobutylphenyl)propanoate (7), the ester of ibuprofen with quercetin, is the most potent derivative. It is an effective antioxidant, inhibits cyclooxygenases 1/2 and lipoxygenase activity and reduces carrageenan induced paw oedema by 61%. It also decreases triglyceride and total cholesterol levels by 69 and 48%, respectively. The results of this study indicate that proper molecular modifications of non steroidal anti-inflammatory drugs may offer a useful route to potent anti-inflammatory agents, which, in addition, acquire a series of biological properties able to prevent or restore a number of pathological changes in multicausal conditions like the metabolic syndrome.