Unprecedented carbonic anhydrase inhibition mechanism: Targeting histidine 64 side chain through a halogen bond
Archiv der Pharmazie,
Год журнала:
2025,
Номер
358(1)
Опубликована: Янв. 1, 2025
Abstract
2,2′‐Thio‐bis(4,6‐dichlorophenol),
namely
bithionol,
is
a
small
molecule
endowed
with
multifaceted
bioactivity.
Its
peculiar
polychlorinated
phenolic
structure
makes
it
suitable
candidate
to
explore
its
potentialities
in
establishing
interaction
patterns
enzymes
of
MedChem
interest,
such
as
the
human
carbonic
anhydrase
(hCA)
metalloenzymes.
Herein,
bithionol
was
tested
on
panel
specific
hCAs
through
stopped‐flow
technique,
showing
promising
micromolar
inhibitory
activity
for
hCA
II
isoform.
X‐ray
crystallographic
studies
revealed
an
unprecedented
halogen‐bond
between
one
chlorine
and
N3(ε)
atom
catalytically
active
histidine
residue,
His64.
Then,
quantum
mechanics
calculations
based
fragment
molecular
orbital
method
allowed
us
estimate
strength
this
bond
(~2.9
kcal/mol)
highlighted
contribution
rich
hydrophobic
network
within
isoenzyme.
Interestingly,
compound
inactivity
against
III
isoform,
characterized
by
His64Lys
Leu198Phe
mutations,
supported
key
role
played
halogen
bonding
enzyme
affinity.
This
finding
might
pave
way
development
new
class
inhibitors
chemical
features,
being
ligand–receptor
interaction.
Язык: Английский
Synthesis, characterization, biological evaluation, ADMET, and molecular docking studies of novel chalcone-sulfonate hybrid compounds as potential antioxidant and antiobesity activities
Journal of Molecular Structure,
Год журнала:
2025,
Номер
unknown, С. 141638 - 141638
Опубликована: Фев. 1, 2025
Язык: Английский
6,7-Dimethoxy-2-methyl-4-substituted quinazolines: Design, synthesis, EGFR inhibitory activity, in vitro cytotoxicity, and in silico studies
European Journal of Medicinal Chemistry,
Год журнала:
2025,
Номер
290, С. 117502 - 117502
Опубликована: Март 15, 2025
Язык: Английский
-Derivatization of Natural Tropolone and β-Thujaplicin Leading to effective Inhibitors of Human Carbonic Anhydrases IX and XII
European Journal of Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown, С. 117552 - 117552
Опубликована: Март 1, 2025
Язык: Английский
A scaffold repositioning approach: dihydroBenzoImidazoTriazineDione (BITD) derivatives as selective ALDH1A1 inhibitors
Molecular Diversity,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 4, 2025
Язык: Английский
A Journey Around Boronic Acids: Sulfonyl Hydrazone‐Containing Derivatives as Carbonic Anhydrase Inhibitors
Chemical Biology & Drug Design,
Год журнала:
2025,
Номер
105(4)
Опубликована: Апрель 1, 2025
ABSTRACT
Recently,
a
rising
interest
in
boronic
acids
and
their
derivatives
was
recorded
the
Medicinal
Chemistry
field
due
to
high
versatility
broad
applicability
as
bioactive
compounds
several
diseases,
including
cancer
microbial
infections.
The
ability
of
acid
moieties
bind
zinc
ions
first
hypothesized
by
inhibitory
activity
bortezomib,
boron‐containing
protease
inhibitor,
on
different
isoforms
Carbonic
Anhydrase
(CA,
EC:
4.2.1.1)
enzyme
family
then
assessed
through
X‐ray
crystallographic
studies
benzoxaboroles
complex
with
hCA
II.
These
findings,
along
overexpression
IX
XII
hypoxic
and,
particular,
breast
cancer,
drove
us
explore
chemical
space
around
phenylboronic
generating
focused
library
16
(1–4a–d)
decorated
alkyl
sulfonyl
hydrazones.
were
subjected
stopped
flow‐based
inhibition
assays
panel
hCAs,
tumor‐associated
isoforms,
revealing
low
micromolar
constants
(
K
I
s)
some
cases.
However,
antiproliferative
conducted
human
triple‐negative
cell
line
showed
lack
at
tested
concentrations.
Язык: Английский
Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors
ACS Medicinal Chemistry Letters,
Год журнала:
2024,
Номер
15(6), С. 972 - 978
Опубликована: Май 23, 2024
In
this
study,
a
focused
library
of
oxime
ester
derivatives
2,4-dichloro-5-sulfamoylbenzoic
acid
(lasamide)
containing
Schiff
bases
was
synthesized
and
tested
in
vitro
for
their
ability
to
inhibit
the
cytosolic
human
carbonic
anhydrases
(hCAs)
I
II,
as
well
transmembrane
tumor-associated
IX
XII
isoforms.
As
result,
we
obtained
first
line
knowledge
on
lasamide
potentially
useful
development
CA
inhibitors
(CAIs).
particular,
our
attention
derivative
11,
which
selective
toward
hCAs
over
isoenzymes.
An
silico
study
conducted
assess
binding
mode
11
within
XII.
Also,
antiproliferative
assays
highlighted
promising
derivatives.
The
data
are
currently
use
better-performing
compounds
Язык: Английский
Exploring heterocyclic scaffolds in carbonic anhydrase inhibition: a decade of structural and therapeutic insights
RSC Advances,
Год журнала:
2024,
Номер
14(48), С. 35769 - 35970
Опубликована: Янв. 1, 2024
Heterocyclic
compounds
represent
a
prominent
class
of
molecules
with
diverse
pharmacological
activities.
Язык: Английский
Privileged Scaffold Hybridization in the Design of Carbonic Anhydrase Inhibitors
Molecules,
Год журнала:
2024,
Номер
29(18), С. 4444 - 4444
Опубликована: Сен. 19, 2024
Human
Carbonic
Anhydrases
(hCA)
are
enzymes
that
contribute
to
cancer’s
development
and
progression.
Isoforms
IX
XII
have
been
identified
as
potential
anticancer
targets,
and,
more
specifically,
hCA
is
overexpressed
in
hypoxic
tumor
cells,
where
it
plays
an
important
role
reprogramming
the
metabolism.
With
aim
find
new
inhibitors
towards
isoforms,
hybridization
of
privileged
scaffolds
isatin,
dihydrothiazole,
benzenesulfonamide
was
investigated
order
explore
how
may
affect
activity
selectivity
isoforms.
In
this
respect,
a
series
isatin
thiazolidinone
hybrids
designed
synthesized
their
biological
on
I,
II,
IX,
explored.
The
compounds
exhibited
promising
inhibitory
results
isoforms
nanomolar
range,
which
has
highlighted
importance
substituents
ring
position
3
5
thiazolidinone.
particular,
compound
5g
most
active
toward
while
5f
potent
inhibitor
within
series.
When
both
potency
were
considered,
appeared
one
promising.
Additionally,
our
investigations
supported
by
molecular
docking
experiments,
putative
binding
poses
compound.
Язык: Английский