Drug Development Research,
Journal Year:
2023,
Volume and Issue:
84(8), P. 1624 - 1651
Published: Sept. 11, 2023
Alzheimer's
disease
(AD)
is
a
progressive
age-related
neurodegenerative
brain
disorder,
which
leads
to
loss
of
memory
and
other
cognitive
dysfunction.
The
underlying
mechanisms
AD
pathogenesis
are
very
complex
still
not
fully
explored.
Cholinergic
neuronal
loss,
accumulation
amyloid
plaque,
metal
ions
dyshomeostasis,
tau
hyperphosphorylation,
oxidative
stress,
neuroinflammation,
mitochondrial
dysfunction
major
hallmarks
AD.
current
treatment
options
for
acetylcholinesterase
inhibitors
(donepezil,
rivastigmine,
galantamine)
NMDA
receptor
antagonists
(memantine).
These
FDA-approved
drugs
mainly
provide
symptomatic
relief
without
addressing
the
pathological
aspects
progression.
So,
there
an
urgent
need
novel
drug
development
that
only
addresses
basic
but
also
shows
neuroprotective
property.
Various
research
groups
across
globe
working
on
multifunctional
agents
amelioration
using
different
core
scaffolds
their
design,
carbamate
among
them.
Rivastigmine
was
first
investigated
management.
fragment,
scaffold
act
as
potential
inhibitor
acetylcholinesterase.
In
this
review,
we
summarize
last
10
years
conducted
modification
with
substituents
primarily
target
ChE
inhibition,
reduce
modulate
Aβ
aggregation.
Journal of Medicinal Chemistry,
Journal Year:
2021,
Volume and Issue:
64(10), P. 6856 - 6876
Published: May 11, 2021
Butyrylcholinesterase
(BChE)
has
been
considered
as
a
potential
therapeutic
target
for
Alzheimer's
disease
(AD)
because
of
its
compensation
capacity
to
hydrolyze
acetylcholine
(ACh)
and
close
association
with
Aβ
deposit.
Here,
we
identified
S06-1011
(hBChE
IC50
=
16
nM)
S06-1031
25
highly
effective
selective
BChE
inhibitors,
which
were
proved
be
safe
long-acting.
Candidate
compounds
exhibited
neuroprotective
effects
the
ability
improve
cognition
in
scopolamine-
Aβ1–42
peptide-induced
cognitive
deficit
models.
The
best
candidate
increased
level
ghrelin,
substrate
BChE,
can
function
improving
mental
mood
appetite.
weight
gain
S06-1011-treated
group
remarkably
increased.
Hence,
inhibition
not
only
plays
protective
role
against
dementia
but
also
exerts
great
effect
on
treating
nursing
care.
Pharmaceuticals,
Journal Year:
2022,
Volume and Issue:
15(12), P. 1560 - 1560
Published: Dec. 14, 2022
Alzheimer’s
disease
(AD)
is
a
neurodegenerative
disorder
characterized
by
decreased
synaptic
transmission
and
cerebral
atrophy
with
appearance
of
amyloid
plaques
neurofibrillary
tangles.
Cognitive,
functional,
behavioral
alterations
are
commonly
associated
the
disease.
Different
pathophysiological
pathways
AD
have
been
proposed,
some
which
interact
influence
one
another.
Current
treatment
for
mainly
involves
use
therapeutic
agents
to
alleviate
symptoms
in
patients.
The
conventional
single-target
approaches
do
not
often
cause
desired
effect
due
its
multifactorial
origin.
Thus,
multi-target
strategies
since
undertaken,
aim
simultaneously
target
multiple
targets
involved
development
AD.
In
this
review,
we
provide
an
overview
pathogenesis
current
drug
therapies
Additionally,
rationales
examples
drugs
pharmacological
actions
against
also
discussed.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(8), P. 7258 - 7258
Published: April 14, 2023
Alzheimer's
disease
(AD)
is
a
progressive
neurodegenerative
disorder
that
leads
to
dementia
and
patient
death.
AD
characterized
by
intracellular
neurofibrillary
tangles,
extracellular
amyloid
beta
(Aβ)
plaque
deposition,
neurodegeneration.
Diverse
alterations
have
been
associated
with
progression,
including
genetic
mutations,
neuroinflammation,
blood-brain
barrier
(BBB)
impairment,
mitochondrial
dysfunction,
oxidative
stress,
metal
ion
imbalance.Additionally,
recent
studies
shown
an
association
between
altered
heme
metabolism
AD.
Unfortunately,
decades
of
research
drug
development
not
produced
any
effective
treatments
for
Therefore,
understanding
the
cellular
molecular
mechanisms
underlying
pathology
identifying
potential
therapeutic
targets
are
crucial
development.
This
review
discusses
most
common
promising
discovery.
Furthermore,
it
highlights
role
in
summarizes
mathematical
models
AD,
stochastic
model
effect
Aβ
on
We
also
summarize
treatment
strategies
these
can
offer
clinical
trials.
Biomedicine & Pharmacotherapy,
Journal Year:
2024,
Volume and Issue:
171, P. 116190 - 116190
Published: Jan. 26, 2024
Sinomenine
(SIN),
an
alkaloid
extracted
from
the
Chinese
herbal
medicine
Sinomenium
acutum,
has
great
potential
in
anti-inflammatory,
immune
regulation,
analgesic
and
sedative,
is
already
a
clinical
drug
for
treatment
of
rheumatoid
arthritis
China.
Our
previous
studies
show
SIN
inhibits
inflammation
by
regulating
ɑ7nAChR,
key
receptor
cholinergic
anti-inflammatory
pathway
(CAP),
which
plays
important
role
peripheral
central
nervous
system
inflammation.
Growing
evidence
supports
dysregulation
inflammatory
responses
play
pathogenesis
AD.
The
intervention
effects
on
AD
CAP
homeostasis
brain
gut
were
analyzed
first
time
present
study
using
scopolamine-induced
model
mice.
Behavioral
tests
used
to
assess
cognitive
performance.
neurons
loss,
function,
responses,
biological
barrier
function
mouse
intestinal
tissues
evaluated
through
variety
techniques,
microbiota
was
detected
16SrRNA
sequencing.
results
showed
that
significantly
inhibited
decline,
system,
inflammation,
damage
as
well
flora
disturbance
caused
SCOP
More
importantly,
effectively
regulated
suppress
activation
TLR4/NF-κB
protect
alleviate
impairment.
ACS Chemical Neuroscience,
Journal Year:
2024,
Volume and Issue:
15(9), P. 1828 - 1881
Published: April 22, 2024
Neurodegenerative
diseases
(NDs)
are
one
of
the
prominent
health
challenges
facing
contemporary
society,
and
many
efforts
have
been
made
to
overcome
(or)
control
it.
In
this
research
paper,
we
described
a
practical
one-pot
two-step
three-component
reaction
between
3,4-dihydronaphthalen-1(2H)-one
(1),
aryl(or
heteroaryl)glyoxal
monohydrates
(2a–h),
hydrazine
monohydrate
(NH2NH2•H2O)
for
regioselective
preparation
some
3-aryl(or
heteroaryl)-5,6-dihydrobenzo[h]cinnoline
derivatives
(3a–h).
After
synthesis
characterization
mentioned
cinnolines
(3a–h),
in
silico
multi-targeting
inhibitory
properties
these
heterocyclic
scaffolds
investigated
upon
various
Homo
sapiens-type
enzymes,
including
hMAO-A,
hMAO-B,
hAChE,
hBChE,
hBACE-1,
hBACE-2,
hNQO-1,
hNQO-2,
hnNOS,
hiNOS,
hPARP-1,
hPARP-2,
hLRRK-2(G2019S),
hGSK-3β,
hp38α
MAPK,
hJNK-3,
hOGA,
hNMDA
receptor,
hnSMase-2,
hIDO-1,
hCOMT,
hLIMK-1,
hLIMK-2,
hRIPK-1,
hUCH-L1,
hPARK-7,
hDHODH,
which
confirmed
their
functions
roles
neurodegenerative
(NDs),
based
on
molecular
docking
studies,
obtained
results
were
compared
with
wide
range
approved
drugs
well-known
(with
IC50,
EC50,
etc.)
compounds.
addition,
ADMET
prediction
analysis
was
performed
examine
prospective
drug
synthesized
compounds
The
from
studies
ADMET-related
data
demonstrated
that
series
heteroaryl)-5,6-dihydrobenzo[h]cinnolines
especially
hit
ones,
can
really
be
turned
into
potent
core
new
treatment
and/or
due
having
reactionable
locations,
they
able
further
organic
reactions
(such
as
cross-coupling
reactions),
expansion
(for
example,
using
other
types
monohydrates)
makes
avenue
designing
novel
efficient
purpose.
Pharmaceutics,
Journal Year:
2019,
Volume and Issue:
11(2), P. 64 - 64
Published: Feb. 1, 2019
Donepezil
(DPZ)
is
widely
used
in
the
treatment
of
Alzheimer's
disease
tablet
form
for
oral
administration.
The
pharmacological
efficacy
this
drug
can
be
enhanced
by
use
intranasal
administration
because
route
makes
bypassing
blood⁻brain
barrier
(BBB)
possible.
aim
study
was
to
develop
a
nanoemulsion
(NE)
as
well
with
combination
bioadhesion
and
penetration
enhancing
properties
(PNE)
order
facilitate
transport
DPZ
from
nose-to-brain.
Composition
NE
established
using
three
pseudo-ternary
diagrams
PNE
developed
incorporating
Pluronic
F-127
aqueous
phase.
Parameters
such
physical
properties,
stability,
vitro
release
profile,
ex
vivo
permeation
were
determined
both
formulations.
tolerability
evaluated
models.
DPZ-NE
DPZ-PNE
transparent,
monophasic,
homogeneous,
physically
stable
droplets
nanometric
size
spherical
shape.
showed
Newtonian
behavior
whereas
shear
thinning
(pseudoplastic)
observed
DPZ-PNE.
profile
formulations
followed
hyperbolic
kinetic.
prediction
parameters
significantly
higher
DPZ-PNE,
suggesting
polymers
an
effective
strategy
improve
through
nasal
mucosa,
which
consequently
increase
its
bioavailability.
Journal of Medicinal Chemistry,
Journal Year:
2020,
Volume and Issue:
63(17), P. 10030 - 10044
Published: July 28, 2020
To
discover
novel
BChE
inhibitors,
a
hierarchical
virtual
screening
protocol
followed
by
biochemical
evaluation
was
applied.
The
most
potent
compound
8012-9656
(eqBChE
IC50
=
0.18
±
0.03
μM,
hBChE
0.32
0.07
μM)
purchased
and
synthesized.
It
inhibited
in
noncompetitive
manner
could
occupy
the
binding
pocket
forming
diverse
interactions
with
target.
proven
to
be
safe
vivo
vitro
showed
comparable
performance
ameliorating
scopolamine-induced
cognition
impairment
tacrine.
Additionally,
treatment
almost
entirely
recover
Aβ1–42
(icv)-impaired
cognitive
function
normal
level
better
behavioral
than
donepezil.
of
total
amount
confirmed
its
anti-amyloidogenic
profile.
Moreover,
possessed
blood–brain
barrier
(BBB)
penetrating
ability,
long
T1/2,
low
intrinsic
clearance.
Hence,
potential
inhibitor
can
considered
as
promising
lead
for
further
investigation
anti-AD
agents.
