Abstract
Monoamine oxidase B (MAO-B) and nitric oxide synthase (NOS) have both been implicated in the pathology of neurodegenerative diseases. In an attempt to design dual-target-directed drugs that inhibit both these enzymes, a series of pteridine-2,4-dione analogues were synthesised. The compounds were found to be relatively weak NOS inhibitors but showed promising MAO-B activity with 6-amino-5-[(E)-3-(3-chloro-phenyl)-prop-2-en-(E)-ylideneamino]-1,3-dimethyl-1H-pyrimidine-2,4-dione and 6-[(E)-2-(3-chloro-phenyl)-vinyl]-1,3-dimethyl-1H-pteridine-2,4-dione inhibiting MAO-B with IC(50) values of 0.602 and 0.314 microM, respectively. The pteridine-2,4-dione analogues thus show promise as scaffolds for the development of potent reversible MAO-B inhibitors and as observed in earlier studies, the most potent inhibitors were obtained with 3-chlorostyryl substitution.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Catalytic Domain
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Computer Simulation
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Crystallography, X-Ray
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Drug Design
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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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Molecular Conformation
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Monoamine Oxidase / chemistry*
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Monoamine Oxidase / metabolism
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Monoamine Oxidase Inhibitors / chemical synthesis*
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Monoamine Oxidase Inhibitors / chemistry
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Monoamine Oxidase Inhibitors / pharmacology
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Neurodegenerative Diseases / drug therapy
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Nitric Oxide Synthase / antagonists & inhibitors*
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Nitric Oxide Synthase / metabolism
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Papio
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Pteridines / chemical synthesis*
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Pteridines / chemistry
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Pteridines / pharmacology
Substances
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Enzyme Inhibitors
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Monoamine Oxidase Inhibitors
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Neuroprotective Agents
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Pteridines
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Nitric Oxide Synthase
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Monoamine Oxidase