The National Institute on Aging of national Institute of Health (NIH) has recently estimated that more than 5.5 million Americans, mostly 65 or older, might have dementia caused by Alzheimer’s. Scientists have not found a clear cause of Alzheimer’s, but they suggest it could be due to a combination of genetic, environmental, and lifestyle factors that possibly trigger this condition. A common hypothesis is based about cholinergic effects of acetylcholine, specifically that low amounts of acetylcholine will lead to cognitive decline and eventually lead to Alzheimer’s. Low amounts of acetylcholine are often associated with acetyl choline esterase (AChE), one of the fastest acting enzymes in the human body, because it breaks down the acetylcholine molecule, making the inhibition of acetylcholine esterase the target for treatment. It has been reported enzyme inhibition by metallocenes, as they enhance biding affinity and selectivity. Moreover, ferrocene has proven to participate in important metal-specific modes of action that contribute to the overall therapeutic efficacy of molecules. The specific aims of this project are to synthesize, characterize and perform biological assays of novel ferrocenyl analogues of one of the two main drugs currently used to treat Alzheimer’s as AChE inhibitors. It is expected that ferrocene moiety will enhance the lipophilicity, bioavailability, and inhibitory activity of these drugs. Claisen-Schmidt condensations and Heck couplings have proven successful reactions to synthesize these analogues. By applying a variety of synthetic techniques such as solvent-free, room temperature, and reflux conditions we have determined the best methodology to achieve higher purity and yield for the synthesized derivatives. Two derivatives of the donepezil drug have been successfully obtained with a moderate and good yield of 49 and 85 %. The third derivative is under optimization process. The methodology, characterization, and bioassays results will be elaborated.

Donepezil ferrocenyl derivatives of acetylcholine esterase inhibitors for the treatment of Alzheimer’s

ACS Spring Meeting 2021

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