Methyl analogues of the experimental Alzheimer drug phenserine: Synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action
Qs. Yu et al., Methyl analogues of the experimental Alzheimer drug phenserine: Synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action, J MED CHEM, 44(24), 2001, pp. 4062-4071
With the goal of developing potential Alzheimer's pharmacotherapeutics, we
have synthesized a series of novel analogues of the potent anticholinestera
ses phenserine (2) and physostigmine (1). These derivatives contain methyl
(3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in ea
ch position of the phenyl group of the phenylcarbamoyl moieties, and with N
-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the
inhibitory action of these compounds against human acetylcholinesterase (AC
hE) and butyrylcholinesterase (BChE). An analysis of the structure/antichol
inesterase activity relationship of the described compounds, together with
molecular modeling, confirmed the catalytic triad mechanism of the binding
of this class of carabamate analogues within AChE and BChE and defined stru
ctural requirements for their differential inhibition.