Candida albicans ergosterol disorders as a consequence of the new sulfone derivative action mode

A series of novel sulfone derivatives were synthesized and screened in vitro for their cytotoxicity and antifungal activity with annotated primary mechanism of action (MOA). We prioritized sulfones with high (4-(bromodichloromethylsulfonyl)benzoic acid 4, 4-(difluoromethylsulfonyl)benzoic acid 12), little (3-[4-(bromodichloromethylsulfonyl)phenyl]propanoic acid 8, difluoromethyl 4-methylphenyl sulfone 11, 4-(difluoromethylsulfonyl)benzoic acid 12), or no cytotoxicity of 4-(4-(dichloromethylsulfonyl)benzoic acid 3) and 3-[4-(dichloromethylsulfonyl)phenyl]propanoic acid 7 against mammalian cell lines. 3 was found to be the most potent sulfone against Candida albicans (R_log=7.25 at 128–256 µg/mL). The mutation in the CNB1 gene (1) increased the sensitivity of the C. albicans biofilm to 3; (2) reduced ergosterol production and therefore generated higher susceptibility to 4. Sulfone 4 at 128 µg/mL increased cellular RH-123 fluorescence in the wild-type cells of C. albicans, except CNB1/cnb1∆. Moreover, the uptake of sulfones into the cell was unaffected regardless of the presence or absence of RH-123, and the uptake of sulfones was strictly cell/strain dependent. Both RH123 and sulfones cumulatively competed with one another for access to transporters. Calcineurin played a role in this mechanism.