Abstract
A series of 3-(triazolyl)-coumarins were synthesized and tested as anti-inflammatory agents. It was possible to infer that these compounds do not alter the interaction of LPS with TLR-4 or TLR-2, as the intracellular pathways involved in the TNF-α secretion and COX-2 activity were not affected. Nevertheless, the compounds inhibited iNOS-derived NO production, without affecting the eNOS activity. The outcome of the docking studies showed that π···π interactions with the heme group are important for the iNOS inhibition, thus making compound 3c a promising lead. Moreover, the efficacy of this compound was visualized by the reduced number of neutrophils in the LPS-inflamed subcutaneous tissue. Together, biological and docking data show that triazolyl-substituted coumarins, that can act on iNOS, are a good scaffold to be explored.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
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 / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology*
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Cells, Cultured
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Coumarins / chemical synthesis
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Coumarins / chemistry
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Coumarins / pharmacology*
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Male
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Models, Molecular
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Molecular Structure
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Neutrophils / drug effects
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase Type II / antagonists & inhibitors*
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Nitric Oxide Synthase Type II / metabolism
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Rats
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Rats, Wistar
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / chemistry
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Triazoles / pharmacology*
Substances
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Anti-Inflammatory Agents
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Coumarins
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Enzyme Inhibitors
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Lipopolysaccharides
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Triazoles
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Nitric Oxide
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Nitric Oxide Synthase Type II