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Synthesis and Evaluation of a Series of Bis(pentylpyridinium) Compounds as Antifungal Agents
Author(s) -
Obando Daniel,
Koda Yasuko,
Pantarat Namfon,
Lev Sophie,
Zuo Xiaoming,
Bijosono Oei Johanes,
Widmer Fred,
Djordjevic Julianne T.,
Sorrell Tania C.,
Jolliffe Katrina A.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800331
Subject(s) - cryptococcus neoformans , pyridinium , potency , chemistry , alkyl , cytotoxicity , candida albicans , antifungal , stereochemistry , mode of action , structure–activity relationship , in vitro , biochemistry , biology , organic chemistry , microbiology and biotechnology
A series of bis(4‐pentylpyridinium) compounds with a variety of spacers between the pyridinium headgroups was synthesised, and the antifungal activity of these compounds was investigated. Lengthening the alkyl spacer between the pentylpyridinium headgroups from 12 to 16 methylene units resulted in increased antifungal activity against C. neoformans and C. albicans , but also resulted in increased hemolytic activity and cytotoxicity against mammalian cells. However, inclusion of an ortho ‐substituted benzene ring in the centre of the alkyl spacer resulted in decreased cytotoxicity and hemolytic activity, while maintaining antifungal potency. Replacement of the alkyl and aromatic‐containing spacers by more hydrophilic ethylene glycol groups resulted in a loss of antifungal activity. Some of the compounds inhibited fungal PLB1 activity, but the low correlation of this inhibition with antifungal potency indicates PLB1 inhibition is unlikely to be the predominant mode of antifungal action of this class of compounds, with preliminary studies suggesting they may act via disruption of fungal mitochondrial function.