Background:
The most important cause of dementia affecting elderly people is the Alzheimer’s
disease (AD). Patients affected by this progressive and neurodegenerative disease have
severe memory and cognitive function impairments. Some medicines used for treating this disease
in the early stages are based on inhibition of acetylcholinesterase. Population aging should
contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the
development of new therapeutic entities for the treatment of this disease.
Methods:
The objective of this work is to identify new substances that have spatial structural
similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's
disease, and to evaluate the capacity of inhibition of these new substances against the enzyme
acetylcholinesterase.
Results:
Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones
with different substitutions patterns in three steps and overall yield of up to 59%. These
compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are
able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM.
Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype
AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic
(CAS) and the peripheral site (PAS).
Conclusion:
We described the first study aimed at investigating the biological properties of spirocyclohexadienones
as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which
provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase
inhibitors.
Acetylcholinesterase inhibitors from southern African plants: An overview of ethnobotanical, pharmacological potential and phytochemical research including and beyond Alzheimer's disease treatment
