Abstract
Indole‐pyrazole
hybrids
are
intriguing
due
to
their
potential
for
synergistic
pharmacological
effects,
unlike
molecules
with
only
one
pharmacophore.
This
study
presents
a
one‐pot
synthesis
of
fused
indole‐pyrazole
derivatives,
bis
4a
and
chromone
4b
using
an
aldehyde,
thiosemicarbizide,
indole,
as
anticancer
antidiabetic
agents.
The
synthesized
compounds
were
characterized
Fourier
transform
infrared
(FTIR),
nuclear
magnetic
resonance
(NMR),
time‐of‐flight
mass
spectrometry
(TOF‐MS).
Initially,
mutagenicity
test
was
performed,
the
showed
no
significant
increase
in
revertant
colonies
against
Salmonella
typhimurium
TA
98
100
strains.
In
MTT
assay
cytotoxicity
two
human
cancer
cell
lines,
A549
HepG‐2;
normal
line,
HEK
293.
Compound
high
potency
IC
50
values
18.70
50.07
µg/mL,
respectively,
whereas
both
low
inhibition
level
293
at
µg/mL.
vitro
α‐amylase
α‐glucosidase,
compound
demonstrated
excellent
3.9
µg/mL
12.1
respectively.
Journal of Enzyme Inhibition and Medicinal Chemistry,
Год журнала:
2024,
Номер
39(1)
Опубликована: Июнь 24, 2024
Inhibition
of
α-glucosidase
and
α-amylase
are
key
tactics
for
managing
blood
glucose
levels.
Currently,
stronger,
more
accessible
inhibitors
needed
to
treat
diabetes.
Indeno[1,2-b]
quinoxalines-carrying
thiazole
hybrids
1–17
were
created
described
using
NMR.
All
analogues
tested
hypoglycaemic
effect
against
STZ-induced
diabetes
in
mice.
Compounds
4,
6,
8,
16
the
most
potent
among
synthesised
analogues.
These
examined
their
effects
on
plasma
insulin,
urea,
creatinine,
GSH,
MDA,
ALT,
AST,
total
cholesterol.
Moreover,
these
compounds
enzymes
vitro.
The
four
represented
moderate
activity
with
IC50
values
0.982
±
0.04,
10.19
0.21
inhibition
17.58
0.74
121.6
5.14
μM
when
compared
standard
medication
acarbose
IC50=0.316
0.02
31.56
1.33
inhibition.
Docking
studies
as
well
silico
ADMT
done.
Abstract
The
design
and
synthesis
of
novel
cytotoxic
agents
is
still
an
interesting
topic
for
medicinal
chemistry
researchers
due
to
the
unwanted
side
effects
anticancer
drugs.
In
this
study,
a
series
uracil–azole
hybrids
were
designed
synthesized.
activity,
along
with
computational
studies:
molecular
docking,
dynamic
simulation,
density
functional
theory,
ADME
properties
also,
evaluated.
compounds
synthesized
by
using
3-methyl-6-chlorouracil
as
starting
material.
Cytotoxicity
was
determined
MTT
assay
in
breast
carcinoma
cell
line
(MCF-7)
Hepatocellular
(HEPG-2).
These
derivatives
demonstrated
powerful
inhibitory
activity
against
hepatocellular
lines
comparison
Cisplatin
positive
control.
Among
these
compounds,
4j
displayed
best
selectivity
profile
good
IC
50
values
16.18
±
1.02
7.56
5.28
µM
MCF-7
HEPG-2
respectively.
Structure–activity
relationships
revealed
that
variation
potency
affected
various
substitutions
benzyl
moiety.
docking
output
showed
bind
well
active
site
EGFR
formed
stable
complex
protein.
DFT
used
investigate
reactivity
descriptors
4a
.
outputs
can
be
considered
potential
agents.
Drug Development Research,
Год журнала:
2025,
Номер
86(2)
Опубликована: Март 28, 2025
ABSTRACT
Recently,
there
has
been
an
increasing
interest
in
the
use
of
protein
kinase
inhibitors
as
a
therapeutic
strategy
for
treatment
cancer.
In
this
study,
new
series
2
H
‐chromene
derivatives
(
‐
5
and
6
8
)
3
‐benzo[
f
]chromene
carbohydrazide
derivative
9
were
synthesized.
The
structure
designed
was
characterized
by
IR,
1
H/
13
C
NMR,
elemental
analysis.
Moreover,
cytotoxic
activity
newly
synthesized
chromenes
evaluated
against
breast
cancer
cell
lines
(MDA‐MB‐231
MCF‐7)
cervical
line
(HeLa).
results
these
evaluations
demonstrated
promising
activity,
ranging
from
good
to
moderate.
Additionally,
lung
fibroblast
(WI‐38),
normal
line,
also
utilized
assess
active
derivatives'
selectivity.
Among
compounds
tested,
chromene
highest
potency,
exhibiting
IC
50
values
5.36
±
0.50,
7.82
0.60,
9.28
0.70
µM
MDA‐MB
231,
MCF‐7,
HeLa
lines,
respectively.
potential
chromone
multi‐targeted
anticancer
agent
assessed
evaluating
its
BRAF
VEGFR‐2.
Notably,
most
significant
VEGFR2
with
value
0.224
compared
sorafenib's
0.045
µM,
while
inhibitory
1.695
relative
Vemurafenib's
0.468
µM.
addition,
compound
inhibits
DHFR
enzyme
2.217
0.014
methotrexate
(IC
=
0.4315
0.019
µM).
These
revealed
that
multifaceted
mechanisms
action
may
augment
effectiveness.
causes
overexpression
caspase‐3
Bax
6.13
8.85‐fold,
It
downregulates
antiapoptotic
Bcl‐2
level
0.4775‐fold
untreated
231
cells.
Flow
cytometry
analysis
MDA‐MB‐231
cells
indicates
induces
cycle
arrest
G0‐G1
phase,
observed
percentage
73.15%.
in‐silico
toxicity
prediction
profile.
Finally,
molecular
docking
studies
supported
findings
confirming
strong
binding
affinities
VEGFR‐2,
BRAF,
DHFR.
