TY - JOUR
TI - 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 potential therapeutic approach against atherosclerosis
AU - Matralis, A.N.
AU - Bavavea, E.-I.
AU - Incerpi, S.
AU - Pedersen, J.Z.
AU - Kourounakis, A.P.
JO - Current Medicinal Chemistry
PY - 2016
VL - 23
TODO - 30
SP - null
PB - Bentham Science Publishers B.V.
SN - 0929-8673
TODO - 10.2174/0929867323666160814001803
TODO - 1,4 benzoxazine derivative;  antiinflammatory agent;  antilipemic agent;  antioxidant;  benzothiazine derivative;  cyclooxygenase 1;  cyclooxygenase 2;  low density lipoprotein cholesterol;  morpholine derivative;  quercetin;  triacylglycerol;  unclassified drug;  1,4-benzothiazine;  antilipemic agent;  antioxidant;  benzoxazine derivative;  morpholine derivative;  nonsteroid antiinflammatory agent;  thiazine derivative, animal experiment;  animal model;  antiinflammatory activity;  antioxidant activity;  atherosclerosis;  cholesterol blood level;  controlled study;  drug activity;  drug screening;  enzyme inhibition;  human;  human cell;  hyperlipidemia;  hypolipidemic activity;  IC50;  in vitro study;  in vivo study;  male;  monocyte;  mouse;  nonhuman;  Review;  triacylglycerol blood level;  animal;  atherosclerosis;  chemical structure;  chemistry, Animals;  Anti-Inflammatory Agents, Non-Steroidal;  Antioxidants;  Atherosclerosis;  Benzoxazines;  Humans;  Hypolipidemic Agents;  Molecular Structure;  Morpholines;  Thiazines
TODO - In line with our previous studies, we have developed through a rational design approach novel morpholine and benzoxa(or thia)zine lead compounds that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) interact 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 cycloxygenase-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 μM. Furthermore, after their long-term administration, compounds 6 and 8 afforded a 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. © 2016 Bentham Science Publishers.
ER -