Structural Modification of Antifungal Acylphloroglucinols against Cryptococcus Species

Abstract

A previously reported natural product-derived acylphloroglucinol, 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropylbenzyl)phenyl)propan-1-one (1), exhibited potent in vitro antifungal activity against Cryptococcus species, the causative agents of life-threatening cryptococcosis. To further investigate the structure−activity relationships (SAR) of this scaffold, structural modifications were undertaken through variation of the acyl substituent, diversification of the aromatic side chain, and functionalization of phenolic hydroxyl group, affording 14 analogues (2−15). Six compounds (5, 6, 8, 11, 12, and 14) displayed improved or comparable antifungal activity against Cryptococcus neoformans (ATCC 208821 and ATCC 90113) and Cryptococcus gattii (ATCC 32609), with MIC values ranging from 0.8 to 14.3 μM. Among them, compound 12 was the most potent analogue, exhibiting MIC values of 0.8−1.0 μM against C. neoformans and 7.9 μM against C. gattii. SAR analysis indicated that hydrophobic substituents of appropriate size and aromatic character were important determinants of antifungal activity. Compounds 1 and 11 decreased intracellular ATP levels in a dose-dependent manner across all three Cryptococcus strains, suggesting impairment of cellular energy metabolism. Molecular docking studies predicted favorable interactions of compounds 1 and 11 with the Saccharomyces cerevisiae cytochrome bc1 complex (Complex III), indicating that cytochrome bc1 may represent a potential molecular target of this acylphloroglucinol series. These findings identify acylphloroglucinols as a promising class of antifungal leads and provide valuable SAR insights for their further optimization.