Developing Novel Coumarin-Containing Azoles Antifungal Agents by the Scaffold Merging Strategy for Treating Azole-Resistant Candidiasis

Abstract

The extensive use of antifungal drugs has resulted in severe drug resistance, making clinical treatment of fungal infections more difficult. Biofilm inhibitors can overcome drug resistance by inhibiting fungal biofilm formation. In this study, some coumarins with antibiofilm activity were merged into CYP51 inhibitors to produce novel molecules possessing potent antiresistance activity. As expected, most compounds exhibited excellent in vitro antifungal activity against pathogenic fungi, especially fluconazole-resistant candidiasis. Then, their mechanism was confirmed by sterol composition analysis and morphological observation. Biofilm inhibition and down-regulation of resistancerelated genes were employed to confirm the compounds' antiresistance mechanisms. Significantly, compound A32 demonstrated fungicidal activity against fluconazole-resistant strain 904. Most importantly, compound A32 showed potent in vivo antifungal activity against pathogenic fungi and fluconazole-resistant strains. Preliminary pharmacokinetic and toxicity tests demonstrated that the compounds possessed favorable druggability. Taken together, compound A32 represents a promising lead to develop novel antifungal agents for treating azole-resistant candidiasis.

From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency In Vitro and In Vivo

“…Furthermore, transmission electron microscopy (TEM) was used to confirm the effect of compounds on fungal ultrastructers. , In the control group (Figure A,C, and E), normal C. albicans cells have regular ellipse structures with dense mannan coats in cell walls and smooth cell membranes.…”

“…Furthermore, transmission electron microscopy (TEM) was used to confirm the effect of compounds on fungal ultrastructers. 35,36 In the control group (Figure 9A,C, and E), normal C. albicans cells have regular ellipse structures with dense mannan coats in cell walls and smooth cell membranes. After treatment with 28 (Figure 9B,D,F), the mannan layer became thinner while the inner β-glucan layer was swollen, suggesting an architecture remodeling happened in fungal cell walls.…”

Syntheses, reactivity, and biological applications of coumarins

“…In 2023, Gou et al employed an alternative approach to avoid resistance ( Yan et al, 2023 ). Specifically, certain coumarin derivatives endowed with antibiofilm activity were combined with CYP51 inhibitors to synthesize novel compounds with robust antifungal capabilities and reduced susceptibility to resistance.…”

Design, synthesis and evaluation of 2-phenylpyrimidine derivatives as novel antifungal agents targeting CYP51

“…16,17 Fungal cells primarily depend on ergosterol for their membrane sterol, whereas mammalian cells rely on cholesterol for their functions. 18–20 The enzyme lanosterol 14α-demethylase (CYP51) is a key part of ergosterol biosynthesis, making it a promising target for antifungal drugs. 21–24…”