title: New multifunctional Di-tert-butylphenoloctahydro(pyrido/benz)oxazine derivatives with antioxidant, antihyperlipidemic, and antidiabetic action.
abstract: Oxidative stress, inflammation, and hyperlipidemia are common factors involved in the pathophysiology of atherosclerosis and type 2 diabetes. We have previously developed multifunctional antidyslipidemic derivatives with antioxidant and antiatherogenic properties. We now report the design, synthesis, and evaluation of two such novel derivatives that incorporate a structural moiety of the antidiabetic agent succinobucol. The new compounds exhibited a much improved in vitro antioxidant and squalene synthase inhibitory activity (at lower micromolar concentrations) as well as a significant antihyperlipidemic effect, reducing plasma total cholesterol, triglycerides, and MDA by 65-90%. Compound 2 also indicated a good anti-inflammatory activity, decreasing edema by 44%, while it was further evaluated for its antidiabetic activity using a type 2 diabetes experimental mouse model. After 7 weeks of administration, it produced a significant antihyperglycemic and antihyperlipidemic activity. In conclusion, rational drug design led to a compound combining improved antioxidant, antidyslipidemic, and antidiabetic action that may serve as a potential therapeutic strategy in metabolic syndrome disorders.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Ladopoulou
authors.forename: Alexios N
authors.initials: AN
authors.lastname: Matralis
authors.forename: Angeliki P
authors.initials: AP
authors.lastname: Kourounakis
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011341:Probucol / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D013186:Farnesyl-Diphosphate Farnesyltransferase; C471047:succinobucol; D011341:Probucol