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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antioxidants / chemical synthesis*
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Antioxidants / pharmacology*
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Atherosclerosis / drug therapy
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Biphenyl Compounds
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Carrageenan
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Cholesterol, Dietary / pharmacology
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Cyclooxygenase Inhibitors / chemical synthesis
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Cyclooxygenase Inhibitors / pharmacology
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Diet, High-Fat
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Drug Design
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Edema / chemically induced
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Edema / prevention & control
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / pharmacology*
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In Vitro Techniques
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Indicators and Reagents
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Lipid Peroxidation / drug effects
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Magnetic Resonance Spectroscopy
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Male
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Mice
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Microsomes / drug effects
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Microsomes / metabolism
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Phenothiazines / chemical synthesis*
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Phenothiazines / pharmacology*
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Picrates
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Rats
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antioxidants
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Biphenyl Compounds
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Cholesterol, Dietary
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Cyclooxygenase Inhibitors
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Enzyme Inhibitors
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Hypolipidemic Agents
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Indicators and Reagents
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Phenothiazines
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Picrates
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Carrageenan
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1,1-diphenyl-2-picrylhydrazyl
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Farnesyl-Diphosphate Farnesyltransferase