Journal of Enzyme Inhibition and Medicinal Chemistry,
Год журнала:
2022,
Номер
37(1), С. 1568 - 1576
Опубликована: Май 29, 2022
The
treatment
of
chronic
neuropathic
pain
remains
one
the
most
challenging
all
neurological
diseases
and
very
much
an
art.
There
exists
no
consensus
for
optimal
management
this
condition
at
moment.
Gaining
inspiration
from
recent
studies
which
pointed
out
involvement
brain-associated
carbonic
anhydrase
(CA,
EC
4.2.1.1)
isoform
VII
in
pathology
various
neurodegenerative
diseases,
highlighted
relationship
between
selective
inhibition
isozyme
relieve
pain,
herein
we
report
synthesis
CA
inhibitory
activity
novel
4-(3-alkyl/benzyl-guanidino)benzenesulfonamides.
Ten
benzyl-substituted
five
alkyl-substituted
4-guanidinobenzenesulfonamide
derivatives
were
obtained,
some
(7c,
7h,
7m
7o)
exhibited
satisfactory
selectivity
towards
over
I
II,
with
KI-s
subnanomolar
range
good
indexes
inhibiting
target
versus
off-target
isoforms.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(2), С. 1611 - 1623
Опубликована: Янв. 11, 2024
As
a
progressive
neuropathic
condition,
glaucoma
can
cause
lifelong
blindness
if
left
untreated.
Novel
phenylpyridazine-tethered
sulfonamides
were
designed
as
selective
inhibitors
for
carbonic
anhydrase
(CA)
isoform
II
to
find
effective
therapeutic
agents
glaucoma.
Subsequently,
the
target
synthesized
and
assessed
their
inhibitory
action
against
cytosolic
CA
I
II.
Interestingly,
molecules
poorly
inhibited
while
exhibiting
low
subnanomolar
potency
Compound
Journal of Enzyme Inhibition and Medicinal Chemistry,
Год журнала:
2023,
Номер
38(1)
Опубликована: Апрель 25, 2023
In
this
work,
new
isatin-based
sulphonamides
(6a-i,
11a-c,
12a-c)
were
designed
and
synthesised
as
potential
dual
VEGFR-2
carbonic
anhydrase
inhibitors
with
anticancer
activities.
Firstly,
all
target
isatins
examined
for
in
vitro
antitumor
action
on
NCI-USA
panel
(58
tumour
cell
lines).
Then,
the
most
potent
derivatives
CA
inhibitory
towards
physiologically
relevant
hCA
isoforms
I,
II,
tumour-linked
IX
isoform,
addition,
activity
was
evaluated.
The
failed
to
inhibit
that
could
be
attributable
steric
effect
of
neighbouring
methoxy
group,
whereas
they
displayed
effect.
Following
that,
11b
12b
tested
their
influence
cycle
disturbance,
apoptotic
potential.
Finally,
detailed
molecular
modelling
analyses,
including
docking
dynamics,
carried
out
assess
binding
mode
stability
isatins.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(9), С. 7406 - 7430
Опубликована: Апрель 20, 2024
A
dual-targeting
approach
is
predicted
to
yield
better
cancer
therapy
outcomes.
Consequently,
a
series
of
coumarin-based
thiazoles
(5a–h,
6,
and
7a–e)
were
designed
constructed
as
potential
carbonic
anhydrase
(CA)
VEGFR-2
suppressors.
The
inhibitory
actions
the
target
compounds
assessed
against
CA
isoforms
IX
VEGFR-2.
assay
results
showed
that
5a,
5d,
5e
can
effectively
inhibit
both
targets.
cytotoxic
effects
tested
on
pancreatic,
breast,
prostate
cells
(PANC1,
MCF7,
PC3).
Further
mechanistic
investigation
disclosed
ability
interrupt
PANC1
cell
progression
in
S
stage
by
triggering
apoptotic
cascade,
seen
increased
levels
caspases
3,
9,
BAX,
alongside
Bcl-2
decline.
Moreover,
vivo
efficacy
compound
an
antitumor
agent
was
evaluated.
Also,
molecular
docking
dynamics
displayed
distinctive
interactions
between
binding
pockets.
RSC Medicinal Chemistry,
Год журнала:
2024,
Номер
15(6), С. 1929 - 1941
Опубликована: Янв. 1, 2024
In
the
last
decades,
carbonic
anhydrases
(CAs)
have
become
top
investigated
innovative
pharmacological
targets
and,
in
particular,
isoforms
IX
and
XII
been
widely
studied
due
to
evidence
of
their
overexpression
hypoxic
tumors.
The
frantic
race
find
new
anticancer
agents
places
quick
preparation
large
libraries
putative
bioactive
compounds
as
basis
a
successful
drug
discovery
development
programme.
this
context,
multi-component
general,
one-step
reactions
are
becoming
very
popular
among
them,
Biginelli's
reaction
gave
clean
easy-to-isolate
products.
Thus,
we
synthesized
series
products
(10-17a-b)
similar
derivatives
(20-21)
bearing
benzenesulfonamide
moiety,
which
is
known
inhibit
CA
enzymes.
Through
stopped-flow
technique,
were
able
assess
ability
targeted
CAs
nanomolar
range
with
promising
selectivity
over
physiologically
relevant
I
II.
Crystallography
studies
docking
simulations
helped
us
gain
insight
into
interaction
patterns
established
enzyme-inhibitor
complex.
From
chemical
similarity-based
screening
in-house
compounds,
diphenylpyrimidine
(23)
emerged.
surprisingly
potent
inhibitory
activity
23
for
along
its
strong
antiproliferative
effect
on
two
(triple-negative
breast
cancer
MDA-MB-231
glioblastoma
U87MG)
cell
lines
laid
foundation
further
investigation,
again
confirming
key
role
cancer.
ACS Omega,
Год журнала:
2023,
Номер
8(8), С. 7666 - 7683
Опубликована: Фев. 17, 2023
With
a
"less
is
more"
philosophy,
series
of
15
chalcone-sulfonamide
hybrids
were
designed
anticipating
synergistic
anticancer
activity.
The
aromatic
sulfonamide
moiety
was
included
as
known
direct
inhibitor
carbonic
anhydrase
IX
activity
through
its
zinc
chelating
property.
chalcone
incorporated
an
electrophilic
stressor
to
indirectly
inhibit
cellular
Screening
by
the
Developmental
Therapeutics
Program
National
Cancer
Institute,
NCI-60,
revealed
that
12
derivatives
potent
inhibitors
cancer
cell
growth
in
multiple
lines
and
promoted
five-dose
screen.
inhibition
profile
indicated
sub-
two-digit
micromolar
potency
(GI50
down
0.3
μM
LC50
low
4
μM)
against
colorectal
carcinoma
cells,
particular.
Unexpectedly,
most
compounds
demonstrated
moderate
catalytic
vitro,
with
4d
being
potent,
having
average
Ki
value
μM.
Compound
4j
showed
ca.
six-fold
selectivity
over
other
tested
isoforms
vitro.
Cytotoxicity
both
live
HCT116,
U251,
LOX
IMVI
cells
under
hypoxic
conditions
confirmed
their
targeting
Elevation
oxidative
stress
stipulated
from
increase
Nrf2
ROS
levels
4j-treated
carcinoma,
compared
control.
arrested
cycle
HCT116
at
G1/S
phase.
In
addition,
up
50-fold
non-cancerous
HEK293T
cells.
Accordingly,
this
study
presents
new,
synthetically
accessible,
simplistically
potential
candidates
be
further
developed
therapeutics.
