title: Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: exploiting phenothiazine's strong antioxidant activity.
abstract: Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation 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.forename: Angeliki P
authors.initials: AP
authors.lastname: Kourounakis
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy; D001713:Biphenyl Compounds; D002351:Carrageenan; D002791:Cholesterol, Dietary / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D059305:Diet, High-Fat; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D015227:Lipid Peroxidation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010851:Picrates; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001713:Biphenyl Compounds; D002791:Cholesterol, Dietary; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D007202:Indicators and Reagents; D010640:Phenothiazines; D010851:Picrates; D002351:Carrageenan; C004931:1,1-diphenyl-2-picrylhydrazyl; D013186:Farnesyl-Diphosphate Farnesyltransferase