Journal of Medicinal Chemistry,
Journal Year:
2018,
Volume and Issue:
61(4), P. 1646 - 1663
Published: Feb. 5, 2018
The
enzyme
butyrylcholinesterase
(BChE)
and
the
human
cannabinoid
receptor
2
(hCB2R)
represent
promising
targets
for
pharmacotherapy
in
later
stages
of
Alzheimer's
disease.
We
merged
pharmacophores
both
into
small
benzimidazole-based
molecules,
investigated
SARs,
identified
several
dual-acting
ligands
with
a
balanced
affinity/inhibitory
activity
an
excellent
selectivity
over
hCB1R
hAChE.
A
homology
model
hCB2R
was
developed
based
on
crystal
structure
used
molecular
dynamics
studies
to
investigate
binding
modes.
In
vitro
proved
agonism.
Unwanted
μ-opioid
affinity
could
be
designed
out.
One
well-balanced
selective
hBChE
inhibitor/hCB2R
agonist
showed
superior
vivo
lead
CB2
regards
cognition
improvement.
data
shows
possibility
combine
molecule
GPCR-activity/enzyme
inhibition
therapy
AD
may
help
rationalize
development
other
ligands.
Archives of Toxicology,
Journal Year:
2019,
Volume and Issue:
93(9), P. 2491 - 2513
Published: Aug. 22, 2019
Alzheimer's
disease
(AD)
is
a
multifactorial
neurodegenerative
disorder,
characterized
by
the
formation,
aggregation
and
accumulation
of
amyloid
beta,
perturbed
metal
(copper,
iron
zinc)
homeostasis,
metal-induced
oxidative
stress,
neuroinflammation,
aberrant
activity
acetylcholinesterase
(AChE)
other
pathologies.
The
aim
this
review
to
discuss
current
therapies
based
on
"combination-drugs-multitargets"
strategy
target
multiple
pathologies
block
progression
pathogenesis
AD.
In
addition
cholinergic
targets,
significant
effort
focused
targeting
stress
component
disease.
main
focus
research
modifications
existing
drugs
with
specific
biological
activity.
Tacrine
was
first
AChE
inhibitor
be
introduced
into
clinical
practice
has
been
frequently
used
for
design
multitarget-directed
ligands.
A
number
hybrid
compounds
containing
tacrine
structural
moieties
derived
from
natural
sources
such
as
flavonoids
[quercetin,
rutin,
coumarin,
gallamine,
resveratrol,
scutellarin,
anisidine,
hesperetin,
(−)-epicatechin]
molecules
(melatonin,
trolox)
have
also
applied
function
Most
these
hybrids
are
potent
inhibitors
butyrylcholinesterase
amyloid-beta
aggregation.
addition,
antioxidant
functionality,
represented
coumarins,
melatonin
reduces
level
via
ROS-scavenging
mechanisms,
well
chelation
redox-active
Cu
Fe,
thus
suppressing
formation
ROS
Fenton
reaction.
Various
medicinal
plants
under
investigation
their
ability
ameliorate
symptoms
therapeutic
potency
huperzine
B,
ginseng,
curcumin
manifested
predominantly
inhibitory
action
toward
AChE,
or
radical-scavenging
redox
metal-chelating
activity,
inhibition
tau-protein
hyperphosphorylation
antiinflammatory
Flavonoids
not
only
antioxidants
agents,
but
interact
protein
kinase
lipid
signaling
pathways,
others
involving
mitogen-activated
kinase,
NF-kappaB
tyrosine
kinase.
Among
most
promising
group
substances
potential
against
AD
flavonoids,
including
myricetin,
morin,
quercetin,
fisetin,
kaempferol,
apigenin
glycitein,
which
shown,
in
vitro,
possess
antiamyloidogenic
fibril-destabilization
being
able
act
chelators
stress.
terms
use
multifunctional
hybrids,
herbal
AD,
some
remaining
challenges
establish
ideal
dose
develop
effective
formulations
preserve
bioavailability
determine
stage
when
they
should
administered.
If
onset
could
delayed
decade,
victims
would
significantly
reduced.
ACS Medicinal Chemistry Letters,
Journal Year:
2018,
Volume and Issue:
9(3), P. 171 - 176
Published: Feb. 9, 2018
Designing
multitarget-directed
ligands
(MTDLs)
is
considered
to
be
a
promising
approach
address
complex
and
multifactorial
maladies
such
as
Alzheimer's
disease
(AD).
The
concurrent
inhibition
of
the
two
crucial
AD
targets,
glycogen
synthase
kinase-3β
(GSK-3β)
human
acetylcholinesterase
(hAChE),
might
represent
breakthrough
in
quest
for
clinical
efficacy.
Thus,
novel
family
GSK-3β/AChE
dual-target
inhibitors
was
designed
synthesized.
Among
these
hybrids,
2f
showed
most
profile
nanomolar
inhibitor
on
both
hAChE
(IC50
=
6.5
nM)
hGSK-3β
kinase
activity
66
nM).
It
also
good
inhibitory
effect
β-amyloid
self-aggregation
(inhibitory
rate
46%)
at
20
μM.
Western
blot
analysis
revealed
that
compound
inhibited
hyperphosphorylation
tau
protein
mouse
neuroblastoma
N2a-Tau
cells.
In
vivo
studies
confirmed
significantly
ameliorated
cognitive
disorders
scopolamine-treated
ICR
mice
less
hepatotoxicity
than
tacrine.
This
study
provides
new
leads
assessment
GSK-3β
AChE
pathway
dual
strategy
treatment.
Journal of Medicinal Chemistry,
Journal Year:
2021,
Volume and Issue:
64(8), P. 4972 - 4990
Published: April 8, 2021
The
multifactorial
nature
of
Alzheimer's
disease
(AD)
is
a
reason
for
the
lack
effective
drugs
as
well
basis
development
"multi-target-directed
ligands"
(MTDLs).
As
cases
increase
in
developing
countries,
there
need
new
that
are
not
only
but
also
accessible.
With
this
motivation,
we
report
first
sustainable
MTDLs,
derived
from
cashew
nutshell
liquid
(CNSL),
an
inexpensive
food
waste
with
anti-inflammatory
properties.
We
applied
framework
combination
functionalized
CNSL
components
and
well-established
acetylcholinesterase
(AChE)/butyrylcholinesterase
(BChE)
tacrine
templates.
MTDLs
were
selected
based
on
hepatic,
neuronal,
microglial
cell
toxicity.
Enzymatic
studies
disclosed
potent
selective
AChE/BChE
inhibitors
(5,
6,
12),
subnanomolar
activities.
X-ray
crystal
structure
5
complexed
BChE
allowed
rationalizing
observed
activity
(0.0352
nM).
Investigation
BV-2
cells
revealed
antineuroinflammatory
neuroprotective
activities
6
(already
at
0.01
μM),
confirming
design
rationale.
