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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 )...
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Published in: | Medicinal chemistry research 2024, Vol.33 (6), p.964-976 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 1054-2523 1554-8120 |
DOI: | 10.1007/s00044-024-03234-y |