Abstract
Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer’s disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure–activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC50 = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.
Highlights
Alzheimer’s disease (AD) is one of the most prevalent forms of late-life mental failure in humans
AChE is a dominant factor for ACh metabolism (80%), acetylcholinesterase inhibitors (AChEIs) can efficiently prevent the hydrolysis of ACh and provide promising therapeutic effects20
We notice that several derivatives of cinnamic acid, such as ferulic acid, caffeic acid, are reported to benefit the treatment of AD for many reasons
Summary
Alzheimer’s disease (AD) is one of the most prevalent forms of late-life mental failure in humans. The target compounds are synthesised and evaluated for their ChEs inhibitory activities. We designed a series of tacrine-cinnamic acid hybrids, and discussed the SAR for these compounds as dual site ChEs inhibitors.
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