In line with our previous studies, novel morpholine and benzoxa(or thia)zine
lead compounds have been developed through a rational design that modulate a multiplicity
of targets against atherosclerosis. We have evaluated the most promising compounds for
their efficiency to a) intercept and scavenge free radicals, b) inhibit the metal ion (Cu2+)-
induced LDL oxidation c) act intracellularly as antioxidants in THP-1 monocytes from a
leukemic patient and d) inhibit the pro-inflammatory enzymes cyclooxygenase-1 (COX-1)
and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their
potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice.
Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited
a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity
at 20 μΜ. In addition, after their long-term administration, compounds 6 and 8 afforded
considerable activity in a chronic experimental animal model of hyperlipidemia (after high
fat diet administration). The multifunctional pharmacological profile exhibited by the compounds
of this study renders them interesting lead compounds for the development of novel
agents against atherosclerosis.
Keywords: Design, synthesis, oxidative stress, lipid peroxidation, microsomes, LDL oxidation, squalene synthase
inhibitors, cyclooxygenase-1 and -2 inhibitors, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol,
atherosclerosis, high fat diet, multifunctional agents.
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