A total of 20 derivatives (1–20) of the crinane-type alkaloid ambelline
were synthesized. These
semisynthetic derivatives were assessed for their potency to inhibit
both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).
To predict central nervous system (CNS) availability, logBB was calculated,
and the data correlated well with those obtained from the parallel
artificial membrane permeability assay (PAMPA). All compounds should
be able to permeate the blood–brain barrier (BBB) according
to the obtained results. A total of 7 aromatic derivatives (5, 6, 7, 9, 10,
12, and 16) with different substitution patterns
showed inhibitory potency against human serum BuChE (IC50 < 5 μM), highlighting the three top-ranked compounds as
follows: 11-O-(1-naphthoyl)ambelline (16), 11-O-(2-methylbenzoyl)ambelline (6), and 11-O-(2-methoxybenzoyl)ambelline (9) with IC50 values of 0.10 ± 0.01, 0.28 ± 0.02,
and 0.43 ± 0.04 μM, respectively. Notably, derivatives 6, 7, 9, and 16 displayed
selective human BuChE (hBuChE) inhibition profiles
with a selectivity index > 100. The in vitro results were supported
by computational studies predicting plausible binding modes of the
compounds in the active sites of hBuChE.
Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease recognized as the most common form of dementia among elderly people. Due to the fact that the exact pathogenesis of AD still remains to be fully elucidated, the treatment is only symptomatic and available drugs are not able to modify AD progression. Considering the increase in life expectancy worldwide, AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. Due to their complex nitrogen-containing structures, alkaloids are considered to be promising candidates for use in the treatment of AD. Since the introduction of galanthamine as an antidementia drug in 2001, Amaryllidaceae alkaloids (AAs) and further isoquinoline alkaloids (IAs) have been one of the most studied groups of alkaloids. In the last few years, several compounds of new structure types have been isolated and evaluated for their biological activity connected with AD. The present review aims to comprehensively summarize recent progress on AAs and IAs since 2010 up to June 2021 as potential drugs for the treatment of AD.
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