title: Antihyperlipidemic morpholine derivatives with antioxidant activity: An investigation of the aromatic substitution.
abstract: Drugs affecting more than one target could result in a more efficient treatment of multifactorial diseases as well as fewer safety concerns, compared to a one-drug one-target approach. Within our continued efforts towards the design of multifunctional molecules against atherosclerosis, we hereby report the synthesis of 17 new morpholine derivatives which structurally vary in terms of the aromatic substitution on the morpholine ring. These derivatives simultaneously suppress cholesterol biosynthesis through SQS inhibition (IC50 values of the most active compounds are between 0.7 and 5.5 μM) while exhibiting a significant protection of hepatic microsomal membranes against lipid peroxidation (with IC50 values for the most active compounds being between 73 and 200 μM). Further evaluation of these compounds was accomplished in vivo in an animal model of acute experimental hyperlipidemia, where it was observed that compounds reduced the examined lipidemic parameters (TC, TG and LDL) by 15-80%. In order to examine the mode of binding of these molecules in the active catalytic site of SQS, we also performed docking simulation studies. Our results indicate that some of the new compounds can be considered interesting structures in the search for new multifunctional agents of potential application in atherosclerosis.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece.
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Ladopoulou
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: Anastasios
authors.initials: A
authors.lastname: Nikitakis
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece. Electronic address: angeliki@pharm.uoa.gr.
authors.forename: Angeliki P
authors.initials: AP
authors.lastname: Kourounakis
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D004195:Disease Models, Animal; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy / Q000473:pathology; D000960:Hypolipidemic Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats
chemical_list: D000975:Antioxidants; D000960:Hypolipidemic Agents; D009025:Morpholines; C037574:morpholine; D013186:Farnesyl-Diphosphate Farnesyltransferase
keywords: Aromatic morpholine derivatives; Docking; Lipid peroxidation; Lipidemic parameters; Multifunctional; Squalene synthase inhibitor