New cholinesterase inhibitors:: synthesis and structureactivity relationship studies of 1,2-benzisoxazole series and novel imidazolyl-d2-isoxazolines

The syntheses of a series of 3-(4-substituted-1-piperidinyl)-6-halo-1,2-benzisoxazole hydrochlorides (5a-b, 6a-b and 7a-b) and 3-(2-butyl-4-chloro-1H-imidazolyl)-substituted-d(2)-isoxazolines (10c-i)by novel methods are described. The inhibitory activity of acety1cholinesterase (AChE) for the newly synthesized compounds against targets from different species, such as pure electric eel AChE, human serum AChE and rat brain AChE, was studied using Ellman et al.'s method. The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzyl functionality present in the N-benzylpiperidine class of inhibitors. Structure-activity relationships were studied by comparing the basicities of the different substituted heterocyclic ring systems at the C-3 position of the 1,2-benzisoxazoles derivatives. Maximum cholinesterase enzyme inhibition was revealed when there was a 6-fluoro substituent on the 1,2-benzisoxazole ring. The 1-morpholine hydrochloride substituent appeared less significant, although in most cases 5a, 6a and 10c evoked maximum potency compared with the existing drug neostigmine. The most potent cholinesterase compound was found to be 1-[2-[6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole}ethyl]piperidine monohydrochloride (5a) by in vitro studies. Copyright (c) 2005 John Wiley & Sons, Ltd.