Dialkyl phenyl phosphates as novel selective inhibitors of butyrylcholinesterase.
A series of dialkyl phenyl phosphates (DAPPs) were synthesized and evaluated in silico and in vitro for inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Among the compounds examined, several DAPPs were shown to be potent inhibitors of butyrylcholinesterase, while having little activity against acetylcholinesterase. The most potent and selective inhibitors were di-n-butyl phenyl phosphate (K(i)=43 microM), di-n-pentyl phenyl phosphate (K(i)=6 microM), and di-cyclohexyl phenyl phosphate (K(i)=7 microM), the first which was shown to be a competitive inhibitor while the latter two being partial competitive inhibitors. Flexible docking simulations suggested that relative binding affinities generally increased as a function of alkyl chain length, while the strength and nature of inhibitory activity depended on whether the compound bound deeply or midway in the active site gorge, or in the proposed peripheral site.
Law
Ken-Shing
KS
Department of Chemistry and Biochemistry, California State University-Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA.
Acey
Roger A
RA
Smith
Cameron R
CR
Benton
David A
DA
Soroushian
Sheila
S
Eckenrod
Brett
B
Stedman
Rachael
R
Kantardjieff
Katherine A
KA
Nakayama
Kensaku
K
D002091:Butyrylcholinesterase / Q000737:chemistry / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D002091:Butyrylcholinesterase