Abstract
A new highly selective inhibitor of acetylcholinesterase (AChE) was discovered by high-throughput screening. Compound 1 was synthesized from a natural product, the N-3-isobutyrylcycloxobuxidine-F 2. A new extraction protocol of this compound is described. The hemisynthesis and optimization of 1 are reported. The analogs of 1 were tested in vitro for the inhibition of both cholinesterases (AChE and BuChE). These compounds selectively inhibited AChE. Extensive molecular docking studies were performed with 2 and AChE employing Discover Biosym software to rationalize the binding interaction. The results suggested that ligand 2 binds simultaneously to both catalytic and peripheral sites of AChE.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry*
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Animals
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Benzoxazines / chemical synthesis*
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Benzoxazines / chemistry
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Binding Sites
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Butyrylcholinesterase / chemistry
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Catalytic Domain
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Cattle
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / chemistry
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Crystallography, X-Ray
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Electrophorus
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Humans
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Models, Molecular*
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Molecular Structure
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Species Specificity
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Structure-Activity Relationship
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Torpedo
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Triterpenes / chemical synthesis*
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Triterpenes / chemistry
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Triterpenes / isolation & purification
Substances
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10-(1-(dimethylamino)ethyl)-1,4a,5,7,7a,9,9a,10,11,12,12a,12b,13,14,14a,14b-hexadecahydro-11-hydroxy-9a,12,a,14b-trimethyl-3-(1-methylethyl)-8H-indeno(5',4'-4,5)cyclohepta(1,2-f)(3,1)benzoxazin-8-one
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Benzoxazines
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Cholinesterase Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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N-(20-(dimethylamino)-16-hydroxy-4-(hydroxymethyl)-4,14-dimethyl-11-oxo-9,19-cyclopregnan-3-yl)-2-methylpropanamide
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Triterpenes
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Acetylcholinesterase
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Butyrylcholinesterase