Molecules,
Journal Year:
2024,
Volume and Issue:
29(22), P. 5314 - 5314
Published: Nov. 11, 2024
Alzheimer's
disease
(AD)
involves
a
complex
pathophysiology
with
multiple
interconnected
subpathologies,
including
protein
aggregation,
impaired
neurotransmission,
oxidative
stress,
and
microglia-mediated
neuroinflammation.
Current
treatments,
which
generally
target
single
subpathology,
have
failed
to
modify
the
disease's
progression,
providing
only
temporary
symptom
relief.
Multi-target
drugs
(MTDs)
address
several
aggregation
of
pathological
proteins.
In
this
review,
we
cover
hybrid
molecules
published
between
2014
2024.
We
offer
an
overview
strategies
employed
in
drug
design
approaches
that
led
notable
improvements
reduced
hepatotoxicity.
Our
aim
is
insights
into
potential
development
new
drugs.
This
highlights
multi-target
featuring
heterocycles
Antioxidants,
Journal Year:
2025,
Volume and Issue:
14(2), P. 123 - 123
Published: Jan. 21, 2025
Alzheimer’s
disease
(AD)
is
a
widely
recognized
type
of
dementia
that
leads
to
progressive
cognitive
decline
and
memory
loss,
affecting
significant
number
people
their
families
worldwide.
Given
the
multifactorial
nature
AD,
multitarget-directed
ligands
(MTDLs)
hold
promise
in
developing
effective
drugs
for
AD.
Phosphodiesterase-9
(PDE9)
emerging
as
promising
target
AD
therapy.
In
this
study,
by
combining
PDE9
inhibitor
C33
with
antioxidant
melatonin,
we
designed
discovered
series
pyrazolopyrimidinone
derivatives
simultaneously
inhibit
possess
activities.
Molecular
docking,
together
dynamics
simulations,
were
applied
accelerate
compound
design
reduce
synthetic
work.
Four
out
14
compounds
validated
inhibitors
comparable
activity.
Notably,
17b
17d
demonstrated
IC50
values
91
89
nM
against
PDE9,
respectively,
good
activities
(ORAC
(Trolox)
2.00
2.60).
This
work
provides
new
approach
designing
MTDLs
treatment
offers
insights
further
structural
modifications
capacities.
Alzheimer's
disease
(AD)
incurs
heavy
costs
for
both
the
population
and
health
systems.
Nevertheless,
drugs
available
only
provide
minimal
symptomatic
management
without
much
impact
on
patients'
quality
of
life.
The
multifactorial
character
AD
suggests
that
development
new
therapies
modulating
multiple
biological
targets
contributing
to
progression
will
more
efficiently
treat
disease.
success
targeting
amyloid-beta
oligomers
this
is
a
valid
approach
efficacious
AD.
Here,
we
report
design
evaluation
series
arylpyrazolone
compounds
their
activity
against
Aβ
aggregation
toxicity
oxidative
stress.
lead
compound
(1)
has
an
EC50
value
270
nM,
good
blood-brain
barrier
permeation
in
vivo
promising
bioavailability.
This
study
demonstrates
potential
these
arylpyrazolones
as
novel,
potentially
effective,
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 27, 2025
Abstract
Microproteins,
short
functional
peptides
encoded
by
small
genes,
are
emerging
as
critical
regulators
of
cellular
processes,
yet
their
roles
in
mitochondrial
function
and
neurodegeneration
remain
underexplored.
In
this
study,
we
identify
NCBP2-AS2
an
evolutionarily
conserved
microprotein
with
significant
energy
metabolism
neurogenesis.
Using
a
combination
molecular
approaches,
including
CRISPR/Cas9
knockout
models,
stoichiometric
co-
immunoprecipitation,
advanced
imaging
techniques,
demonstrate
that
localizes
to
the
inner
space
interacts
translocase
membrane
(TIM)
chaperones.
These
interactions
suggest
role
ATPase
subunit
transport,
supported
observed
reductions
levels
impaired
glucose
NCBP2-AS2-deficient
cells.
zebrafish,
led
increased
astroglial
proliferation,
microglial
abundance,
enhanced
neurogenesis,
particularly
under
amyloid
pathology.
Notably,
show
expression
is
consistently
downregulated
human
Alzheimer’s
disease
brains
zebrafish
amyloidosis
suggesting
neurodegenerative
findings
reveal
novel
link
between
protein
metabolism,
neural
regeneration,
positioning
potential
therapeutic
target
for
mitigating
dysfunction
promoting
neurogenesis
diseases
such
disease.
ChemistrySelect,
Journal Year:
2025,
Volume and Issue:
10(11)
Published: March 1, 2025
Abstract
Fifteen
new
thiazole
derivatives
were
synthesized
and
their
cholinesterase
inhibitory
activities
evaluated.
The
design
of
these
compounds
involves
linking
rings
to
a
cyclopropyl
moiety,
followed
by
substitutions
with
various
amine
groups.
structures
the
thiazole‐cyclopropyl
confirmed
using
IR,
HRMS,
¹H‐NMR,
¹
3
C‐NMR,
HPLC,
single‐crystal
X‐ray
diffraction.
Compounds
6g
6h
found
crystallize
in
monoclinic
system
space
group
P21/c
,
featuring
α
γ
angles
90°.
Cholinesterase
inhibition
was
assessed
Ellman
method.
While
most
exhibited
weak
effects
on
butyrylcholinesterase
(BuChE),
they
showed
significant
acetylcholinesterase
(AChE).
Compound
6l
potent
AChE
activity,
an
IC₅₀
0.079
±
0.16
µM,
comparable
Donepezil
(IC₅₀
=
0.056
0.22
µM).
Molecular
docking,
molecular
dynamics
simulations,
MM/GBSA
binding
free
energy
calculations
stable
interactions
between
compound
peripheral
anionic
site
AChE.
Furthermore,
metal
ion
chelation
studies
demonstrated
that
as
multitarget‐directed
ligand,
effectively
chelated
biologically
relevant
ions.
In
summary,
shows
potential
inhibitor
represents
promising
lead
for
further
research
development
Alzheimer's
disease
treatment.
