Abstract
Twenty one phenylpropanoids (including eugenol and safrole) and synthetic analogues, thirteen of them new compounds, were evaluated for antifungal properties, first with non-targeted assays against a panel of human opportunistic pathogenic fungi. Some structure-activity relationships could be observed, mainly related to the influence of an allyl substituent at C-4, an OH group at C-1 and an OCH3 at C-2 or the presence of one or two NO2 groups in different positions of the benzene ring. All active compounds were tested in a second panel of clinical isolates of C. albicans and non-albicans Candida spp., Cryptococcus neoformans and dermatophytes. The eugenol derivative 4-allyl-2-methoxy-5-nitrophenol (2) was the most active structure against all strains tested, and therefore it was submitted to targeted assays. These studies showed that the antifungal activity of 2 was not reversed in the presence of an osmotic support such as sorbitol, suggesting that it does not act by inhibiting the fungal cell wall synthesis or assembly. On the other hand, the Ergosterol Assay showed that 2 did not bind to the main sterol of the fungal membrane up to 250 µg mL−1. In contrast, a 22% of fungal membrane damage was observed at concentrations = 1 × MIC and 71% at 4× MIC, when 2 was tested in the Cellular Leakage assay. The comparison of log P and MICs for all compounds revealed that the antifungal activity of the eugenol analogues would not to be related to lipophilicity.
Highlights
Fungi have emerged over the past two decades as major causes of human infections, especially among immunocompromised hosts, having an enormous impact on morbidity and mortality [1,2]
This paper suggests that both the propenyl and the allyl moieties appeared to be the minimum requirements for these phenylpropanoids to show antifungal activity
We have reported the antifungal properties in agar dilution assays of a series of phenylpropanoids against yeasts, Aspergillus spp. and dermatophytes [11], finding that 1 and some of its analogues were inactive on all fungal spp. up to 50 μg mL−1
Summary
Fungi have emerged over the past two decades as major causes of human infections, especially among immunocompromised hosts, having an enormous impact on morbidity and mortality [1,2]. Sikemma et al [19] and Gill et al [20] found that the antibacterial mechanism of action of eugenol is the disruption of the cytoplasmic membrane, which could be due to the fact that the phenolic hydroxyl group might increase the solubility of this molecule in aqueous suspensions improving the ability to pass through the hydrophilic portion of the cell envelope This assertion is in clear contradiction to a QSAR study of essential oils’ components performed by Voda et al [21], who found that the best antifungal activities were displayed by the most hydrophobic phenylpropanoids which possess a higher ability to penetrate the walls of fungal cells than the hydrophilic ones. Some targeted assays on the most active structures were used to discriminate whether active compounds damage either the membrane or the wall of the fungal cells and to add new data on the mechanism of antifungal action of this type of compounds
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