title: Balancing Antioxidant, Hypolipidemic and Anti-inflammatory Activity in a Single Agent: The Example of 2-Hydroxy-2-Substituted Morpholine, 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives as a Rational Therapeutic Approach against Atherosclerosis.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens. Greece.
authors.forename: Alexios N
authors.initials: AN
authors.lastname: Matralis
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens. Greece.
authors.forename: Eugenia-Ismini
authors.initials: EI
authors.lastname: Bavavea
authors.affiliation: Department of Sciences, University Roma Tre, Viale G. Marconi, 446, 00146 Roma. Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Incerpi
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Roma. Italy.
authors.forename: Jens Z
authors.initials: JZ
authors.lastname: Pedersen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, 15771 Athens. Greece.
authors.forename: Angeliki P
authors.initials: AP
authors.lastname: Kourounakis
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy*; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C446962:1,4-benzothiazine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D048588:Benzoxazines; D000960:Hypolipidemic Agents; D009025:Morpholines; D013843:Thiazines
keywords: Design; HDL-cholesterol; LDL oxidation; LDL-cholesterol; atherosclerosis; cyclooxygenase-1 and -2 inhibitors; high fat diet; lipid peroxidation; microsomes; multifunctional agents; oxidative stress; squalene synthase
  inhibitors; synthesis; total cholesterol; triglycerides