Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Candida
infection represents a global threat with associated high resistance and mortality rate. Azoles such as the triazole drug fluconazole are the frontline therapy against invasive fungal infections; however, the emerging multidrug-resistant strains limit their use. Therefore, a series of novel azole
UOSO
1-15
derivatives were developed based on a modified natural scaffold to combat the evolved resistance mechanism and to provide improved safety and target selectivity. The antifungal screening against
C. albicans
and
C. auris
showed that
UOSO
10
and
12-14
compounds were the most potent derivatives. Among them,
UOSO
13
exhibited superior potent activity with MIC
50
values of 0.5 and 0.8 μg mL
−1
against
C. albicans
and
C. auris
compared to 25 and 600 μg mL
−1
for fluconazole, respectively.
UOSO
13
displayed significant CaCYP51 enzyme inhibition activity in a concentration-dependent manner with an IC
50
10-fold that of fluconazole, while exhibiting no activity against human CYP50 enzyme or toxicity to human cells. Furthermore,
UOSO
13
caused a significant reduction of
Candida
ergosterol content by 70.3% compared to a 35.6% reduction by fluconazole. Homology modeling, molecular docking, and molecular dynamics simulations of
C. auris
CYP51 enzyme indicated the stability and superiority of
UOSO
13
. ADME prediction indicated that
UOSO
13
fulfils the drug-likeness criteria with good physicochemical properties.
Effective targeting of
Candida
CYP51 enzyme by oxadiazole derivatives following iterated lead optimization using plant cuminaldehyde as a scaffold.
Sprache
–
Identifikatoren
eISSN: 2632-8682
DOI: 10.1039/d2md00196a
Titel-ID: cdi_rsc_primary_d2md00196a
Format
–
Weiterführende Literatur
Empfehlungen zum selben Thema automatisch vorgeschlagen von bX