Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans
Résumé
Candidainfections have become a serious public health problem with high mortalityrates, especially in immunocompromised patients, sinceCandida albicansis the majoropportunistic pathogen responsible for systemic or invasive candidiasis. Commerciallyavailable antifungal agents are restricted and fungal resistance to such drugs hasincreased; therefore, the development of a more specific antifungal agent is necessary.Using assays for antifungal activity, here we report that two new compounds of1,3,4-oxadiazoles class (LMM5 and LMM11), which were discovered byin silicomethodologies as possible thioredoxin reductase inhibitors, were effective againstC. albicans. Both compounds hadin vitroantifungal activity with MIC 32μg/ml.Cytotoxicityin vitrodemonstrated that LMM5 and LMM11 were non-toxic in the cell linesevaluated. The kinetic of the time-kill curve suggested a fungistatic profile and showedan inhibitory effect of LMM5 and LMM11 in 12 h that remained for 24 and 36 h, whichis better than fluconazole. In the murine systemic candidiasis model byC. albicans, thetwo compounds significantly reduced the renal and spleen fungal burden. Accordingto the SEM and TEM images, we hypothesize that the mechanism of action of LMM5and LMM11 is directly related to the inhibition of the enzyme thioredoxin reductaseand internally affect the fungal cell. In view of allin vitroandin vivoresults, LMM5and LMM11 are effective therapeutic candidates for the development of new antifungaldrugs addressing the treatment of human infections caused byC. albicans.