Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

Abstract

Candidiasis, caused by the opportunistic yeast Candida albicans, is the most common fungal infection today. Resistance of C. albicans to current antifungal drugs has emerged over the past decade leading to the need for novel antifungal agents. Our aim was to select new antifungal compounds by library-screening methods and to assess their antifungal effects against C. albicans. After screening 90 potential antifungal compounds from JUNIA, a chemical library, two compounds, 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-3,6-dimethylpyridin-2(1H)-one (PYR) and (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (TRI), were identified as having potential antifungal activity. Treatment with PYR and TRI resulted in a significant reduction of C. albicans bioluminescence as well as the number of fungal colonies, indicating rapid fungicidal activity. These two compounds were also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. PYR and TRI had an inhibitory effect on Candida biofilm formation and reduced the thickness of the mannan cell wall. In a Caenorhabditis elegans infection model, PYR and TRI decreased the mortality of nematodes infected with C. albicans and enhanced the expression of antimicrobial genes that promote C. albicans elimination. Overall, PYR and TRI showed antifungal properties against C. albicans by exerting fungicidal activities and enhancing the antimicrobial gene expression of Caenorhabditis elegans.

Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation

“…Cultures of C. albicans clinical isolates CaCi-2 and CaCi-17 were incubated overnight at 30 °C in YPD with shaking. Overnight cultures of C. albicans were plated onto brain heart infusion (BHI) agar plates containing 50 µg/mL kanamycin by transferring 10 µL of each culture spread over the surface using a plate spreader, and allowed to grow at 30 °C for 16 h. A liquid media-based C. elegans infection assay protocol was used, based on previous studies 83 – 85 . Briefly, 48-well plates were prepared with each well containing either: fluconazole (16 µg/mL for CaCi-2 or 256 µg/mL for CaCi-17), NPD827 (40 µg/mL), fluconazole and NPD827 (16 or 256 µg/mL fluconazole with 40 µg/mL NPD827), or no drug treatment.…”

Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity

“…A liquid media-based C. elegans infection assay protocol was used, based on previous studies. 68 – 70 Briefly, 48-well plates were prepared with each well containing varying concentrations of NPD6433 or no drug treatment. C. elegans were washed twice from NGM plates using 6 mL of M9 buffer with swirling to dislodge worms from agar and transferred to a 15 mL conical tube.…”

The Trisubstituted Isoxazole MMV688766 Exerts Broad-Spectrum Activity against Drug-Resistant Fungal Pathogens through Inhibition of Lipid Homeostasis

“…Plates were incubated at 30°C for 16 h to create fungal lawns. A liquid media-based C. elegans infection assay protocol was used, based on previous studies ( 74 – 76 ). Briefly, 48-well plates were prepared with each well containing either MMV688766 or no drug treatment in infection medium (80% M9 buffer, 20% BHI, 10 μg/mL cholesterol, and 90 μg/mL kanamycin).…”