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 butyrytcholinesterase, while having little activity against acetylcholinesterase. The most potent and selective inhibitors were di-n-butyl phenyl phosphate (K-i = 43 mu M), di-n-pentyl phenyl phosphate (K-i = 6 mu M), and di-cyclohexyl phenyl phosphate (K-i = 7 mu M), 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. (c) 2007 Elsevier Inc. All rights reserved.