Methyl analogues of the experimental Alzheimer drug phenserine: Synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action

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.