Tacrine was the first drug to display beneficial effects on cognitive impairment of Alzheimer
Disease (AD) patients. Unfortunately, many treated patients displayed related hepatotoxicity,
and hence this drug was withdrawn. Notwithstanding, recent efforts have been directed to design
small tacrine analogues targeting the underlying pathogenic mechanisms of AD. In this context, we
have developed a number of pyranotacrines by changing the benzene fused ring in tacrine by a 4Hpyran.
Based on this strategy, in this account we will show the tacrine analogues that we have designed,
synthesized and evaluated as potential multipotent agents for AD in the last years. We have
demonstrated that this approach is possible, and that a number of readily available tacrine analogues
show cholinesterase inhibition power, as well as other pharmacological properties, such as calcium
channel blockade, antioxidant properties, neuroprotection, Aβ-amyloid inhibition aggregation capacity,
etc., making them suitable multipotent molecules for further development for the potential treatment
Keywords: Tacrine, Pyranotacrines, Acetylcholinesterase inhibitors, Butyrylcholinesterase inhibitors, Alzheimer's disease,
Neuroprotection, Multi-Target-Directed Ligands.
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