Synthesis and Evaluation of a Series of Bis(pentylpyridinium) Compounds as Antifungal Agents |
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| Authors: | Dr Daniel Obando Dr Yasuko Koda Namfon Pantarat Dr Sophie Lev Dr Xiaoming Zuo Johanes Bijosono?Oei Dr Fred Widmer Prof Julianne T Djordjevic Prof Tania C Sorrell Prof Katrina A Jolliffe |
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| Affiliation: | 1. School of Chemistry, The University of Sydney, NSW, Australia;2. The University of Sydney, Marie Bashir Institute for Infectious Diseases and Biosecurity, Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW, Australia |
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| Abstract: | 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. |
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| Keywords: | antifungal agents bispyridinium compounds haemolytic activity medicinal chemistry structure– activity relationships |
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