Abstract
A series of new 3-aroylpyrido[1,2-a]pyrimidines were synthesized from aryl methyl ketones in a simple two-step procedure and evaluated as nitric oxide synthases (NOS) inhibitors. In order to perform a structure-activity relationship study, different aroyl groups were introduced in 3-position and methyl groups were introduced at different positions of the pyrimidine heterocycle. Compounds with a biphenyloyl, benzyloxybenzoyl or naphthoyl group displayed the highest inhibitory effects which were further increased by introduction of a methyl group in position 8 of the pyrido[1,2-a]pyrimidine moiety. Some of the compounds exhibited promising inhibitory effects with selectivity toward the purified inducible NOS (iNOS) and were also active against iNOS expressed in stimulated RAW 264.7 cells.
MeSH terms
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Animals
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Cell Line
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Ethylenediamines / metabolism
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Gene Expression Regulation, Enzymologic
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Heme / metabolism
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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NADP / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors*
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Nitric Oxide Synthase / chemistry
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Radioactivity
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Rats
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Structure-Activity Relationship
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Substrate Specificity
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Sulfanilamides / metabolism
Substances
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Enzyme Inhibitors
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Ethylenediamines
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Griess reagent
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Isoenzymes
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Pyrimidines
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Sulfanilamides
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Heme
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NADP
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II