Bioorganic & Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
88-89, P. 117333 - 117333
Published: May 17, 2023
Butyrylcholinesterase
(BuChE)
and
amyloid
β
(Aβ)
aggregation
remain
important
biological
target
mechanism
in
the
search
for
effective
treatment
of
Alzheimer's
disease.
Simultaneous
inhibition
thereof
by
application
multifunctional
agents
may
lead
to
improvement
terms
symptoms
causes
Here,
we
present
rational
design,
synthesis,
evaluation
molecular
modelling
studies
novel
series
fluorene-based
BuChE
Aβ
inhibitors
with
drug-like
characteristics
advantageous
Central
Nervous
System
Multiparameter
Optimization
scores.
Among
17
synthesized
tested
compounds,
identified
22
as
most
potent
eqBuChE
inhibitor
IC50
38
nM
37.4%
at
10
μM.
Based
on
studies,
including
dynamics,
determined
binding
mode
compounds
within
explained
differences
activity
two
enantiomers
compound
22.
A
fluorenyl
meeting
drug-likeness
criteria
seems
be
a
promising
starting
point
further
development
anti-Alzheimer
agents.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(3), P. 2937 - 2937
Published: Feb. 2, 2023
Piperidines
are
among
the
most
important
synthetic
fragments
for
designing
drugs
and
play
a
significant
role
in
pharmaceutical
industry.
Their
derivatives
present
more
than
twenty
classes
of
pharmaceuticals,
as
well
alkaloids.
The
current
review
summarizes
recent
scientific
literature
on
intra-
intermolecular
reactions
leading
to
formation
various
piperidine
derivatives:
substituted
piperidines,
spiropiperidines,
condensed
piperidinones.
Moreover,
applications
natural
piperidines
were
covered,
latest
advances
discovery
biological
evaluation
potential
containing
moiety.
This
is
designed
help
both
novice
researchers
taking
their
first
steps
this
field
experienced
scientists
looking
suitable
substrates
synthesis
biologically
active
piperidines.
ACS Chemical Neuroscience,
Journal Year:
2021,
Volume and Issue:
12(11), P. 2057 - 2068
Published: May 21, 2021
In
Alzheimer's
disease,
neurons
slowly
degenerate
due
to
the
accumulation
of
misfolded
amyloid
β
and
tau
proteins.
our
research,
we
performed
extended
studies
directed
at
aggregation
inhibition
using
in
cellulo
(Escherichia
coli
model
protein
aggregation),
silico,
vitro
kinetic
studies.
We
tested
library
1-benzylamino-2-hydroxyalkyl
multifunctional
anti-Alzheimer's
agents
identified
very
potent
dual
inhibitors.
Among
derivatives,
selected
compound
18,
which
exhibited
a
unique
profile
biological
activity.
This
was
most
balanced
inhibitor
(Aβ42
(inh.)
80.0%,
inh.
68.3%
10
μM),
with
previously
reported
inhibitory
activity
against
hBuChE,
hBACE1,
Aβ
(hBuChE
IC50
=
5.74
μM;
hBACE1
41.6
(aggr.)
3.09
μM).
docking
for
both
proteins,
tried
explain
different
structural
requirements
vs
tau.
Moreover,
showed
that
18
could
inhibit
process
several
steps
also
displayed
disaggregating
properties.
These
results
may
help
design
next
generations
or
selective
Archiv der Pharmazie,
Journal Year:
2023,
Volume and Issue:
356(8)
Published: June 5, 2023
In
this
study,
two
diverse
series
of
2-aminothiazole-based
multitarget
compounds,
one
propenamide
and
the
other
propanamide
derivatives,
were
designed
synthesized.
Subsequently,
their
anticholinesterease
antioxidant
(ORAC)
activities
tested.
Among
them,
compound
3e
was
most
potent
acetylcholinesterase
(AChE)
inhibitor
(AChE
IC50
=
0.5
μM,
butyrylcholinesterase
[BChE]
14.7
μM)
9e
BChE
3.13
0.9
μM).
Kinetic
experiments
showed
that
both
compounds
mixed-type
inhibitors.
According
to
activity
results,
five
(3e,
4e,
5e,
9d,
9e)
selected
for
further
studies,
all
which
are
dual
cholinesterase
Then,
investigated
in
terms
metal
chelation
activity.
Moreover,
neuroprotective
effects
against
H2
O2
-induced
damage
PC12
cell
line
evaluated
at
10
μM
results
effect
53%
compared
with
reference
ferulic
acid
(77%).
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
(MTT)
revealed
noncytotoxic.
Additionally,
more
effective
reducing
lipopolysaccharides-induced
interleukin-1β
(IL-1β),
IL-6,
tumor
necrosis
factor-α
(TNF-α),
nitric
oxide
(NO)
production
human
monocyte
derived
from
patient
acute
monocytic
leukemia
compounds.
Finally,
a
molecular
docking
study
also
performed.
