Bioorganic & Medicinal Chemistry Letters
Novel deoxyvasicinone and tetrahydro-beta-carboline hybrids as inhibitors
of acetylcholinesterase and amyloid beta aggregation
,
c
,
,*
Hongtao Dua *, Xinyu Jianga, Meng Maa, Huili Xua, Shuang Liua, Fang Mab
a College of Life Science, Xinyang Normal University, Xinyang 464000, China
b School of Geographic Sciences, Xinyang Normal University, Xinyang 464000, China
c College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A novel series of deoxyvasicinone-tetrahydro-beta-carboline hybrids were synthesized and evaluated as acetyl-
cholinesterase (AChE) and β-amyloid peptide (Aβ) aggregation inhibitors for the treatment of Alzheimer’s dis-
ease. The results revealed that the derivatives had multifunctional profiles, including AChE inhibition, Aβ1-42
aggregation inhibition, and neuroprotective properties. Inspiringly, hybrids 8b and 8d displayed excellent
Deoxyvasicinone
Tetrahydro-β-carboline
Acetylcholinesterase
β-Amyloid peptide
Alzheimer’s disease
inhibitory activities against hAChE (IC50 = 0.93 and 1.08 nM, respectively) and Aβ1ꢀ 42 self-aggregation (IC50
=
19.71 and 2.05
μ
M, respectively). In addition, 8b and 8d showed low cytotoxicity and good neuroprotective
activity against Aβ1ꢀ 42-induced damage in SH-SY5Y cells.
Alzheimer’s disease (AD) is progressive, fatal, and the most common
neurodegenerative disease. Alzheimer’s Disease International (ADI) es-
timates that more than 50 million people suffered from AD in 2019, a
figure set to increase to 152 million by 2050.1 The causes of AD are not
yet fully understood, but some factors, including neuron loss, Aβ de-
progressive deposition of Aβ plays a crucial role in AD pathogenesis,
which can cause neuronal death and eventually dementia. Therefore,
many series of compounds have been developed as inhibitors of AChE
and Aβ aggregation in recent years.13–15
Natural products are important sources of novel lead compounds
with bioactive properties.16 Deoxyvasicinone (A) and β-carboline (B)
alkaloids (Fig. 1) are the main active ingredients of Peganum harmala,
which possesses many biological activities, including antitumor, anti-
bacterial, and anti-inflammatory activities.17 Recently, deoxyvasicinone
and its derivatives have been researched as cholinesterase inhibitors
(Fig. 1).18–21 For instance, derivatives C and D show potent inhibitory
activity against AChE with IC50 values of 50 and 23 nM, respec-
tively.22,23 Moreover, there is growing evidence that β-carboline de-
rivatives demonstrate potential inhibitory activities against
cholinesterase, monoamine oxidase, and Aβ aggregation.24–26 For
example, derivative E displays an excellent ability to inhibit cholines-
terase (IC50, 21.6 nM for AChE, and 39.8 nM for butyrylcholinesterase
posits, τ-aggregation, neuroinflammation, and oxidative stress, have
been suggested to play significant roles in AD.2–6 Currently, drugs for the
treatment of AD include four acetylcholinesterase inhibitors (tacrine,
donepezil, rivastigmine and galantamine) and one N-methyl-D-aspartate
(NMDA) receptor antagonist (memantine). Unfortunately, these drugs
can only improve symptoms but not cure the disease. Furthermore, side
effects, including nausea, vomiting, and liver damage, have been re-
ported after the use of these drugs.7 Thus, it is necessary to develop more
effective drugs for the treatment of AD.
Due to the complexity of AD and the interconnections of various
factors in its progression, the development of multitarget-directed li-
gands (MTDLs) with two or more disease targets has attracted much
attention as a therapeutic method for the treatment of AD.8,9 Among the
diverse factors of AD, both the low levels of ACh and the deposition of Aβ
play vital roles in AD pathogenesis.10,11 AChE is a key enzyme in the
hydrolysis of acetylcholine. Thus, acetylcholinesterase inhibitors
(AChEIs) could increase the amount of ACh in AD patients. Furthermore,
some researchers have identified that the peripheral anionic site (PAS)
of AChE contributes to accelerating senile Aβ deposition.12 The
(BuChE)), good inhibition of Aβ aggregation (65.8% at 20 μM) and good
antioxidant activity (1.57 Trolox equivalents).27 In addition, Qu et al
reported that a novel series of bivalent β-carboline derivatives (F)
showed good potency for BuChE inhibition, Aβ1-42 disaggregation and
neuroprotection.25 Thus, β-carboline is regarded as a useful framework
for AD drug design. Additionally, a literature study reported that two
naturally occurring dimers (G) of deoxyvasicinone and β-carboline
* Corresponding authors at: College of Life Science, Xinyang Normal University, Xinyang 464000, China (H. Du).
Received 13 May 2020; Received in revised form 30 September 2020; Accepted 27 October 2020
Available online 31 October 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.