New potent acetylcholinesterase inhibitors in the tetracyclic triterpene series.
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.
Sauvaître
Thibault
T
Institut de Chimie des Substances Naturelles, Bt 27, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
Barlier
Mireille
M
Herlem
Denyse
D
Gresh
Nohad
N
Chiaroni
Angèle
A
Guenard
Daniel
D
Guillou
Catherine
C
D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D020134:Catalytic Domain; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004593:Electrophorus; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014101:Torpedo; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification
C524705:10-(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; D048588:Benzoxazines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C524706:N-(20-(dimethylamino)-16-hydroxy-4-(hydroxymethyl)-4,14-dimethyl-11-oxo-9,19-cyclopregnan-3-yl)-2-methylpropanamide; D014315:Triterpenes; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase