Bioorganic & Medicinal Chemistry Letters
Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening,
chemical optimization and molecular modeling studies
,
You Zhoua *, Xin Lub, Chenxi Dub, Yijun Liub, Yifan Wanga, Kwon Ho Hongc, Yao Chend,
,
*
Haopeng Sunb
a College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA
d School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alz-
heimer’s disease (AD), sertaconazole was identified through a combination of structure-based virtual screening
followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and
selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target
proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the
generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study
provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may
benefit the treatment of late stage AD.
Alzheimer’s disease
Multifunctional agents
Butyrylcholinesterase (BuChE)
Indoleamine 2,3-dioxygenase 1 (IDO1)
Sertaconazole
Virtual screening
Docking
Alzheimer’s disease (AD) is a common cause for dementia, charac-
terized by impaired cognitive capacity beyond what could be considered
a consequence of normal aging. It affects the memory, thinking process,
learning ability and other cognitive functions.1 According to the World
Alzheimer Report 2019, there are currently>50 million people living
with AD worldwide. The population of AD will reach 152 million in
2050.2 AD imposes immense suffering on patients and their families and
has become one of the most severe public health issues worldwide.
Although the etiology of AD is not yet entirely known, a variety of
conditions are believed to be implicated in the development of AD such
as aggregation and accumulation of amyloid-β (Aβ), tau-protein aggre-
gation, oxidative stress, and low levels of neurotransmitter acetylcholine
(ACh).3–6 Currently approved AD treatments are based on the cholin-
ergic and anti-glutamatergic mechanisms. Unfortunately, they only
provide temporary and modest improvement in cognitive functions, but
cannot effectively reverse the neuronal injury and death caused by
AD.7,8 Thus, great efforts should be made to develop more effective
therapies to fight the upcoming AD epidemic.
an increasing interest in developing multi-target-directed ligands
(MTDLs) which simultaneously manipulate multiple targets for
improving both therapeutic safety and (or) efficacy. Many multifunc-
tional agents in this field have been reported recently, such as MTDLs
targeting glycogen synthase kinase 3β (GSK3β) and tau aggregation,
MTDLs targeting GSK3β and acetylcholinesterase (AChE), MTDLs tar-
geting AChE and serotonin transporter (SERT), and some of them have
already entered clinical trials.10
It is widely accepted that the cognitive and memory deteriorations
associated with AD are caused by
the decline of ACh.11 There are two types of cholinesterase enzymes,
AChE and butyrylcholinesterase (BuChE), responsible for the hydrolysis
of ACh in the brain. In a healthy brain, AChE is more active than BuChE
and has long been considered as a key target for the development of AD
therapeutics. However, as AD progresses, the AChE level in the brain
decreases progressively while BuChE level remains unchanged or even
increases up to 165% when compared to that of the normal brain.12,13
Hence, in progressed AD, BuChE plays an essential role as a compen-
sating enzyme. In addition, selective BuChE inhibition is able to restore
ACh levels in mice and improve the cognitive performance of mice
Due to the complexity nature of AD and the involvement of multiple
pathologic mechanisms in its progression, traditional drugs that only act
on a single target might not exhibit satisfactory efficacy.9 Thus, there is
treated
with
the
Aβ
peptide,
yet
without
peripheral
* Corresponding authors.
Received 27 September 2020; Received in revised form 14 November 2020; Accepted 16 December 2020
Available online 24 December 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.