Asymmetric Synthesis And Biological Evaluation Of Analogoues And Dimers Of Rivastigmine As Cholinesterase Inhibitors

Alzheimer's disease (AD) is a progressive irreversible disorder of elderly patients which is characterized by widespread central cholinergic neuronal loss which, in turn, results in the loss of cognitive functions. Currently, AD has become one of the biggest killers of the elder people. The past two decades have witnessed a considerable research effort devoted to unraveling the molecular, biochemical, and cellular mechanisms of AD. Several hypotheses have been proposed attempting to explain the pathogenesis of AD, and cholinergic hypothesis is cholinergic hypothesis is widely accepted. To date, the enhancement of the central cholinergic function is the mainly effective approach, mainly by means of acetylcholinesterase (AChE) inhibitors.Rivastigmine in particular, represents a newer-generation inhibitor, approved in 2000 under the trade name of Exelon, endowed with a carbamate structure that made it a slow substrate to react covalently with the active site of the enzyme. Although it is not fully established that the selectivity in inhibiting AChE vs BChE ratio in low peripheral cholinergic effects in AD patients, drugs which can inhibit both AChE and BChE usually show a better biological profile. In this thesis, rivastigmine is used as model compound for structural modifications. Two strategies of modification were provided, one is synthesis of chiral analougs of rivastigmine by instead of dimethylamino using piperidyl, pyrrolidyl, azepanyl. Another is synthesis of dimers of rivastigmine.Based on the methods of asymmetric synthesis of rivastigmine in our previous work, (S)-rivastigmine and twelve chiral analogues were synthesized starting from p-hydroxybenzaldehyde or m-hydroxybenzaldehyde via (R-) or (S-) tert-butanesulfinylimines as a chiral initiator, and characterized by IR,1H NMR,13C NMR and HR-MS techniques. The ee values of the new compounds determined by chiral HPLC up to 80%. The synthesis of dimers of rivastigmine is still under research.Ellman's method was applied to evaluate their bioactivities. Results showed that these compounds exhibited potential inhibitory activities of acetylcholinesterase and butyrylcholinesterase (BChE), some of them even superior to rivastigmine. Some of the new tested compounds have higher selectivity for AChE over BChE, but most of them demonstrated specific BChE inhibitory activity.