Research Square (Research Square),
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 15, 2023
Abstract
A
series
of
8-(piperazin-1-yl)imidazo[
1,2-a
]pyrazine
derivatives
were
designed
and
synthesized
as
acetylcholinesterase
inhibitors
(AChEIs)
antioxidants
for
the
treatment
Alzheimer's
disease
(AD).
Moreover,
biological
evaluation
results
demonstrated
that
these
compounds
exhibited
moderate
inhibitory
activities
toward
(AChE)
radical
scavenging
activities.
Among
them,
23l
was
most
potent
AChE
inhibitor
with
an
IC
50
value
0.55
µM,
which
higherthe
5.01
galantamine
reference
compound;
while
23g
had
best
antioxidant
activity
36.28
lower
than
ascorbic
acid
control
drug.
Furthermore,
molecular
docking
studies
indicate
can
simultaneously
bind
to
both
catalytic
active
site
(CAS)
peripheral
anionic
(PAS)
AChE,
consistent
mixed
inhibition
pattern
shown
by
enzyme
kinetic
studies.
The
interaction’s
stability
23l-AChE/BChE
also
assessed
using
a
conventional
atomistic
100
ns
dynamics
simulation
study,
revealed
conformational
representative
compound
in
cavity
AChE.
In
addition,
properties
all
predicted
online
through
molinspiration
server,
matched
orally
administered
drugs.
Based
on
properties,
AChEIs
is
valuable
further
development.
Chemistry & Biodiversity,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 4, 2025
In
this
study,
a
structurally
directed
pharmacophore
hybridization
technique
is
used
to
combine
the
two
essential
structural
scaffolds
coumarin
and
thiazoles
in
search
of
new
class
acetylcholinesterase
(AChE)
butyrylcholinesterase
(BuChE)
inhibitor
for
Alzheimer's
disease
(AD).
A
library
120
compounds
was
designed
series
5a(1-15),
5b(16-30),
5c(31-45),
5d(46-60),
6a(61-75),
6b(76-90),
6c(91-105),
6d(106-120)
using
various
substituted
phenol,
β-ketoesters,
thiazole
derivatives.
Eleven
were
identified
as
potential
hybrids
molecular
property
filter
analysis
docking
studies,
they
comprise
N-substituted
The
results
indicated
that
5b16
5c35
exhibited
strong
binding
interactions
with
GLY116,
GLY117,
TYR332,
HIS438
(ranging
from
-27.42
-24.18
kcal/mol)
GLY119,
ASP72,
PHE288
-32.21
-25.92
when
tested
against
AChE
(1EVE)
BuChE
(1P0I)
inhibitors.
These
synthesized
via
conventional
methods
characterized
by
different
spectroscopic
methods.
vitro
anti-cholinesterase
activity
compounds,
example,
showed
potent
moderate
IC50
(2.00
±
0.09-29.63
0.48)
µM
(34.93
0.62-17.92
0.42)
µM,
respectively.
Our
study
demonstrated
development
novel
hybrid
derivatives
inhibitors,
these
could
be
utilized
ADs.
Chemical Biology & Drug Design,
Год журнала:
2024,
Номер
104(4)
Опубликована: Окт. 1, 2024
ABSTRACT
Alzheimer's
disease
(AD)
is
a
chronic
progressive,
age‐related
neurodegenerative
brain
disorder
characterized
by
the
irreversible
decline
of
memory
and
other
cognitive
functions.
It
one
major
health
threat
21st
century,
which
affects
around
60%
population
over
age
60
years.
The
problem
this
even
more
because
existing
pharmacotherapies
only
provide
symptomatic
relief
without
addressing
basic
factors
disease.
extracellular
deposition
amyloid
β
(Aβ)
to
form
senile
plaques,
intracellular
hyperphosphorylation
tau
neurofibrillary
tangles
(NFTs).
Due
complex
pathophysiology
disease,
various
hypotheses
have
been
proposed,
including
cholinergic,
Aβ,
tau,
oxidative
stress,
metal–ion
hypothesis.
Among
these,
cholinergic
Aβ
are
primary
targets
for
AD.
Therefore,
continuous
advances
made
in
developing
potential
cholinesterase
inhibitors
N
‐methyl‐D‐aspartate
(NMDA)
receptor
antagonists
delay
progression
restore
neurotransmission.
In
review
article,
we
tried
comprehensively
summarize
recent
advancement
NMDA
antagonist
(memantine)
their
hybrid
analogs
as
disease‐modifying
agents
treatment
Furthermore,
also
depicted
design,
rationale,
SAR
analysis
memantine‐based
hybrids
used
last
decade
ACS Chemical Neuroscience,
Год журнала:
2024,
Номер
15(11), С. 2334 - 2349
Опубликована: Май 15, 2024
Parkinson's
disease
(PD)
is
a
significant
health
issue
because
it
gradually
damages
the
nervous
system.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid
(AMPA)
receptors
play
role
in
development
of
PD.
The
current
investigation
employed
hybrid
benzodioxole-propanamide
(BDZ-P)
compounds
to
get
information
on
AMPA
receptors,
analyze
their
biochemical
and
biophysical
properties,
assess
neuroprotective
effects.
Examining
characteristics
all
subunits
receptor
offers
insights
into
impact
BDZ-P
desensitization
deactivation
rate.
It
demonstrates
partial
improvement
locomotor
capacities
mouse
model
disease.
In
addition,
vivo
experiment
assessed
activity
by
utilizing
open-field
test.
Our
findings
demonstrated
that
BDZ-P7
stands
out
with
its
remarkable
potency,
inhibiting
GluA2
subunit
nearly
8-fold
an
IC50
3.03
μM,
GluA1/2
7.5-fold
3.14
GluA2/3
7-fold
3.19
GluA1
6.5-fold
3.2
significantly
impacting
rate
receptor.
showed
partially
reinstating
abilities
results
above
suggest
show
great
promise
as
top
contenders
for
novel
therapies.
Abstract
Alzheimer's
disease
(AD)
is
a
prevalent
indication
of
dementia
syndrome.
The
syndrome
commonly
manifests
as
AD.
2019
World
Report
estimates
that
there
are
over
50
million
people
worldwide
who
have
dementia,
and
number
projected
to
increase
150
by
2050.
AchE
(Acetylcholinesterase)
BchE
(butyrylcholinesterase)
enzymes
responsible
for
AD,
resulting
in
thinking
difficulties,
memory
loss,
dementia.
Researchers
looking
at
non‐toxic,
bioactive
ChE
inhibitors
found
nature.
Donepezil
galantamine,
example,
exclusively
target
AchE,
while
rivastigmine
tacrine
block
both.
development
potential
anti‐Alzheimer
molecules
has
gained
considerable
attention
recent
years.
Keeping
mind,
this
review
enables
the
synthesis
many
hybrid
analogs
containing
sulfur,
oxygen,
nitrogen
heterocyclic
moiety
barriers
AChE
BuChE
structure
activity
relationship
(SAR).
This
addresses
current
advancements
study
emphasizing
straightforward,
sustainable
synthetic
methods
synthesizing
anti‐AD
their
structure‐activity
relation
Preclinical
early
clinical
phases
highlighted,
research
on
generating
powerful
incredibly
effective
cholinesterase
altering
existing
treat
Drug Development Research,
Год журнала:
2024,
Номер
85(3)
Опубликована: Апрель 16, 2024
One
of
the
worst
long-term
health
issues
past
few
decades
is
Alzheimer's
disease
(AD).
Unfortunately,
there
are
currently
insufficient
choices
for
treating
and
caring
AD,
which
makes
it
a
popular
subject
drug
development
research.
Studies
on
drugs
AD
have
primarily
concentrated
use
multitarget
directed
ligands.
Following
this
strategy,
we
designed
new
ChE
inhibitors
with
additional
antioxidant
metal
chelator
effects.
In
research,
eight
novel
N'-(quinolin-4-ylmethylene)propanehydrazide
derivatives
were
synthesized
characterized.
We
then
evaluated
inhibition
potency
all
final
compounds
cholinesterase
enzymes.
Among
them,
4e
(IC
