Journal of Enzyme Inhibition and Medicinal Chemistry,
Год журнала:
2023,
Номер
38(1)
Опубликована: Июнь 29, 2023
A
chromone-peptidyl
hybrids
series
was
synthesised
and
rationally
repurposed
towards
identification
of
potential
antileishmanial
hits
against
visceral
leishmaniasis.
Three
7c,
7n,
7h
showed
IC50
values
(9.8,
10,
12
µM,
respectively)
which
were
comparable
to
erufosine
(9.8
µM)
but
lower
potency
than
miltefosine
(3.5
µM).
Preliminary
assessment
cytotoxicity
using
human
THP-1
cells
presented
7c
7n
as
non-cytotoxic
up
100
µM
while
had
CC50
19.4
>40
respectively.
In
silico
studies
pinpointed
the
N-p-methoxyphenethyl
substituent
at
peptidyl
moiety
together
with
oxygen-based
substituted
functions
phenyl
ring
chromone
crucial
players
in
binding
LdCALP.
Together,
these
findings
present
anticipated
hit
compounds
for
possible
development
agents
Leishmaniasis,
which
is
caused
by
a
parasitic
protozoan
of
the
genus
Leishmania,
still
major
threat
to
global
health,
impacting
millions
individuals
worldwide
in
endemic
areas.
Chemotherapy
has
been
principal
method
for
managing
leishmaniasis;
nevertheless,
evolution
drug
resistance
offers
significant
obstacle
therapeutic
success.
Drug-resistant
behavior
these
parasites
complex
phenomenon
including
both
innate
and
acquired
mechanisms.
Resistance
frequently
related
changes
transportation,
target
alterations,
enhanced
efflux
from
pathogen.
This
review
revealed
specific
genetic
mutations
Leishmania
that
are
associated
with
commonly
used
antileishmanial
drugs
such
as
pentavalent
antimonials,
miltefosine,
amphotericin
B,
paromomycin,
resulting
gene
expression
along
functioning
various
proteins
involved
uptake,
metabolism,
efflux.
Understanding
linked
essential
creating
approaches
tackling
avoiding
spread
drug-resistant
variants.
Based
on
treatments
focus
pathways
could
potentially
improve
treatment
efficacy
help
long-term
leishmaniasis
control.
More
study
needed
uncover
complete
range
generating
medication
develop
new
therapies
based
available
information.
Journal of Infection and Public Health,
Год журнала:
2024,
Номер
17(5), С. 810 - 818
Опубликована: Март 13, 2024
In
Europe,
up
to
70%
of
visceral
leishmaniasis
(VL)
cases
occurring
in
adults
living
with
HIV.
People
HIV
VL
co-infection
often
display
persistent
parasitemia,
requiring
chronic
intermittent
anti-Leishmania
therapies.
Consequently,
frequent
relapses
and
higher
mortality
rates
are
common
these
individuals.
As
such,
it
is
paramount
importance
understand
the
reasons
for
parasite
persistence
improve
infection
management.
To
outline
possible
causes
treatment
failure
context
HIV-VL,
we
followed
a
person
HIV-VL
nine
years
12-month
period.
We
characterized:
HIV-related
clinicopathological
alterations
(CD4+
T
counts
viremia)
Leishmania-specific
seroreactivity,
quantification
pro-inflammatory
cytokines
upon
stimulation
studied
Leishmania
clinical
isolate
recovered
during
this
The
subject
presented
controlled
viremia
low
CD4+
counts.
remained
PCR
positive
also
seropositive.
cellular
response
antigens
was
erratic.
identified
as
first
infantum
case
evidence
decreased
miltefosine
susceptibility
Portugal.
Treatment
multifactorial
process
driven
by
host
determinants.
Still,
real-time
determination
drug
profiles
isolates
an
unexplored
resource
monitoring
VL.
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Май 21, 2024
Abstract
Leishmaniasis
is
a
disease
caused
by
protozoan
of
the
genus
Leishmania
,
affecting
millions
people,
mainly
in
tropical
countries,
due
to
poor
social
conditions
and
low
economic
development.
First-line
chemotherapeutic
agents
involve
highly
toxic
pentavalent
antimonials,
while
treatment
failure
emergence
drug-resistant
strains.
arginase
(ARG)
enzyme
vital
pathogenicity
contributes
higher
infection
rate,
thus
representing
potential
drug
target.
This
study
helps
designing
ARG
inhibitors
for
leishmaniasis.
Py-CoMFA
(3D-QSAR)
models
were
constructed
using
34
from
different
chemical
classes
against
L.
(L.)
amazonensis
(
La
ARG).
The
3D-QSAR
predictions
showed
an
excellent
correlation
between
experimental
calculated
pIC
50
values.
molecular
docking
identified
favorable
hydrophobicity
contribution
phenyl
cyclohexyl
groups
as
substituents
allosteric
site.
Molecular
dynamics
simulations
selected
protein–ligand
complexes
conducted
understand
derivatives’
interaction
modes
affinity
both
active
sites.
Two
cinnamide
compounds,
7g
7k
identified,
with
similar
structures
reference
4h
site
inhibitor.
These
compounds
can
guide
development
more
effective
antileishmanial
drugs.
Pathogens,
Год журнала:
2023,
Номер
12(7), С. 939 - 939
Опубликована: Июль 15, 2023
In
2020,
the
WHO
established
road
map
for
neglected
tropical
diseases
2021–2030,
which
aims
to
control
and
eradicate
20
diseases,
including
leishmaniosis
Chagas
disease.
addition,
since
2015,
has
been
developing
a
Global
Action
Plan
on
Antimicrobial
Resistance.
this
context,
achievement
of
innovative
strategies
as
an
alternative
replace
conventional
therapies
is
first-order
socio-sanitary
priority,
especially
regarding
endemic
zoonoses
in
poor
regions,
such
those
caused
by
Trypanosoma
cruzi
Leishmania
spp.
infections.
scenario,
it
worth
highlighting
group
natural
peptide
molecules
(AMPs
CPPs)
that
are
promising
improving
therapeutic
efficacy
against
these
zoonoses,
they
avoid
development
toxicity
resistance
treatments.
This
review
presents
novelties
their
ability
cross
whole
system
cell
membranes
well
stimulate
host
immune
defenses
or
even
serve
vectors
molecules.
The
efforts
biotechnological
sector
will
make
possible
overcome
limitations
antimicrobial
peptides
through
encapsulation
functionalization
methods
obtain
approval
treatments
be
used
clinical
programs
eradication
Frontiers in Microbiology,
Год журнала:
2025,
Номер
16
Опубликована: Янв. 30, 2025
Leishmania
is
a
well-known
unicellular
parasite
as
the
causative
agent
of
debilitating
vectorborne
disease
with
diverse
manifestations
from
fatal
visceral
(VL)
and
mucocutaneous
(MCL)
forms
to
self-healing
cutaneous
(CL).
There
an
urgent
need
for
protective
vaccines
also
drug
candidates
due
changes
in
map
endemicity
world-wide
spread
[1].
However,
failure
deep
understanding
real
parasite-host-vector
interaction
has
hampered
development
or
effective
treatments.
Seyed
et
al.
have
discussed
some
underlying
reasons
vaccination
correlates
protection
already
identified
mouse
models
vaccine
formulations
that
better
meet
these
criteria
namely
Live
attenuated
non-pathogenic
species
DNA
vaccines.
The
application
new
technologies
such
CRISPR-Cas9
[2]
generation
antibiotic-free
plasmids
[3]
are
now
available
contribute
solving
inbuilt
drawbacks
associated
platforms.
Basically,
against
other
relevant
macrophage-resident
parasites
Trypanosoma
cruzi
benefit
"concomitant
immunity"
which
means
"persistent,
low-level
infection"
[4][5][6].
Cai
demonstrated
effectiveness
experimental
live
chagas
formulated
on
recombinant
avirulent
major
(dhfr-ts
-)
expresses
antigen.
outcome
study
warrants
further
investigation
live-attenuated
both
leishmaniasis
chagas,
two
globally
important
infections.For
moment,
while
human
lag
behind,
chemotherapy
still
plays
most
role
control.
rising
resistance
current
therapeutics,
urges
chemicals
be
replaced.
Despite
significant
breakthroughs
high
throughput
discovery,
there
identification
promising
novel
anti-leishmania
compounds.
Almeida
Machado
advantaged
repurposing
involves
identifying
therapeutic
uses
existing
drugs
approved
indications
[7].
This
group
presented
first
time
vitro
subtilisin
inhibitor
(PF-429242),
anti-viral
drug,
infantum
parasite.
PF-429242
suppresses
protease
induces
several
cellular
alterations
mitochondrial
damage,
oxidative
stress
autophagy
addition
modulating
host
immune
response.
Recently,
synthetic
biology
come
into
focus
enhance
leishmaniasis,
diagnostic
tools
therapeutics
including
immunetherapeutics.
Synthetic
multidisciplinary
field
science
focuses
living
systems
organisms,
it
applies
engineering
principles
develop
biological
parts,
devices,
redesign
found
nature
[8].
Khandibharad
Singh,
explain
applications
combat
resulted
pre-clinical
achievements
like
circuits
synthekines.
Besides
intensive
Bamorovat
introduced
risk
factors
predispose
meglumine
antimoniate
unresponsiveness
tropica
derived
CL.
Accordingly,
treatment
not
only
dependent
genes
[9]
but
demographical,
clinical
environmental
factors,
response,
adherence
by
patients,
genetic
background
even
RNA
virus
infection
parasites.
Therefore,
any
(existing
upcoming),
regular
monitoring
prevent
crucial
[10].The
last
least
critical
play
evaluating
efficacies
newly
designed
developed
For
species,
preclinical
model
characteristics
missing,
example
no
reported
standardized
specific
[11].
Species
Viannia
subgenus
poorly
infective
mice
generally
asymptomatic
induce
mild
resolves
within
few
weeks
almost
elimination
parasite,
condition
weakly
resembles
[12].
Munoz-Durango
explained
CL
adapted
panamensis
isolate
reproducibly
dermal
very
similar
BALB/c
mice.
They
confirmed
this
suits
pharmacological
interventions
regarding
panamensis.To
conclude,
our
antileishmanial
complete.
necessitates
full
emerging
therapies
maintain
competence
endemic
areas.
Second,
we
must
rush
substitute
unaffordable
high-risk
use
especially
Advanced
single-cell
analysis
controlled
(CHIM)
will
hopefully
make
dream
true
near
future.
Future Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown, С. 1 - 17
Опубликована: Фев. 24, 2025
Aim
Trypanosomatid
diseases,
leishmaniasis
and
trypanosomiasis
are
vector-borne
parasitic
diseases
that
can
cause
death
catastrophic
economic
losses
for
millions
of
people.
The
growing
resistance
trypanosomatid
parasites
to
current
treatments
highlights
the
urgent
need
new
therapeutic
agents.
This
study
explored
5-nitroindole-rhodanine
conjugates
identify
promising
compounds
with
potential
future
development
as
antitrypanosomatid
treatments.