Antifungal Structure–Activity Relationship Studies of Broad-Spectrum Phenothiazines
ACS Omega,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 29, 2025
Fungal
infections
remain
a
critical
unmet
medical
need
with
millions
of
occurring
annually.
With
only
three
classes
antifungal
drugs
available,
drug
resistance
and
modest
activity
toward
some
fungi
represent
threats
to
human
health.
To
address
this,
optimization
the
properties
approved
appropriate
pharmacokinetic
represents
an
attractive
strategy.
Here,
we
have
shown
that
phenothiazine-based
CWHM-974
extends
include
fluconazole-resistant
Candida
albicans,
auris,
Cryptococcus
glabrata,
filamentous
molds
such
as
Aspergillus
fumigatus,
Fusarium
spp.,
Rhizopus
arrhizus,
endemic
fungal
pathogens
Histoplasma
capsulatum,
Blastomyces
dermatitidis,
Coccidioides
spp.
Thus,
phenothiazines
(PTZs)
consistent
broad
range
medically
relevant
fungi,
including
organisms
from
difficult
nearly
impossible
treat
current
drugs.
Unfortunately,
did
not
exhibit
in
vivo
efficacy
either
neoformans
or
C.
albicans
mouse
infection
models,
necessitating
effort
optimize
scaffold
further.
Toward
this
end,
synthesis
minimum
inhibitory
concentration
(MIC)
values
are
reported
for
15
novel
PTZ
analogs
extend
structure-activity
relationships
(SARs).
Six
were
identified
2-
4-fold
more
potent.
Azaphenothiazines
(aza-PTZs)
tolerated
resulted
potent
antifungals
moderate
reduction
lipophilicity
facile
chemical
synthesis.
One
analog
displayed
selectivity
improvement
against
serotonin
5HT2c
receptor
versus
CWHM-974,
but
its
overall
profile
panel
other
dopamine
receptors
improve.
Overall,
broad-spectrum
reduced
neuroreceptor
affinity
PTZ-based
encourages
continued
develop
therapeutic
drug.
Язык: Английский
Analogues of the anti-malaria drug mefloquine have broad spectrum antifungal activity and are efficacious in a model of disseminated Candida auris infection.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 30, 2024
Only
three
classes
of
antifungal
drugs
are
currently
in
clinical
use.
Here,
we
report
that
derivatives
the
malarial
drug
mefloquine
have
broad
spectrum
activity
including
difficult
to
treat
molds
and
endemic
fungi.
Pharmacokinetic
efficacy
studies
NSC-4377
indicate
it
penetrates
central
nervous
system
is
active
against
Язык: Английский
Analogs of the anti-malaria drug mefloquine have broad-spectrum antifungal activity and are efficacious in a model of disseminated Candida auris infection
Antimicrobial Agents and Chemotherapy,
Год журнала:
2024,
Номер
68(11)
Опубликована: Окт. 4, 2024
ABSTRACT
Only
three
classes
of
antifungal
drugs
are
currently
in
clinical
use.
Here,
we
report
that
derivatives
the
malarial
drug
mefloquine
have
broad-spectrum
activity
including
difficult-to-treat
molds
and
endemic
fungi.
Pharmacokinetic
efficacy
studies
NSC-4377
indicate
it
penetrates
central
nervous
system
is
active
against
Candida
auris
vivo
.
These
data
strongly
support
further
development
analogs
as
a
potentially
new
class
molecules.
Язык: Английский