Abstract

Background: Cutaneous and invasive fungal infections are constant threats to human health that substantiate theneed for the development of new efficacious and safe antimycotics.

Methods: A series of N1-alkyl, N1-acyl and N1-sulfonyl derivatives of 4,6- dimethylisoxazolo[3,4-b]pyridin-3(1H)-one (1) were synthesized. The antimicrobial activities of title compounds against 21 pathogenic yeast-like fungal clinical isolates and 5 reference strains were evaluated by means of a broth microdilution method.

Results: Among the compounds tested, the newly prepared N1-benzoyl (2m) and N1-(4-fluorobenzoyl) (2n) derivatives of 1 showed 81% and 95% inhibitory efficacy, respectively, against the clinical isolates, which were comparable to that of the reference drug fluconazole. The strains that exhibited the highest susceptibility to the compound 2n included Candida utilis (MIC < 6.2 g/mL), C. parapsilosis (MIC in the range <6.2 - 12.5 g/mL), Geotrichum candidum (MIC = 12.5 g/mL) as well as C. lusitaniae and Rhodotorula mucilaginosa (MIC = 25 g/mL).

Conclusion: In terms of MIC, compound 2n proved to be four times more active against the clinical isolates of Candida albicans and C. albicans ATCC 10231 standard strain than fluconazole, the widely prescribed antifungal agent for mucosal and systemic yeast infections (MIC = 50 vs 200 g/mL).

Keywords: Antifungal activity, isoxazolo[3, 4-b]pyridin-3(1H)-ones, structure-activity relationships, synthesis.

Graphical Abstract