Antifungal Activity of Eugenol Analogues. Influence of Different Substituents and Studies on Mechanism of Action

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.

Antifungal Activity of Eugenol and its Association with Nystatin on Candida albicans

“…In this study, the osmotic protective effect of sorbitol was not present, since there was no variation in the values of MIC, similarly to a previous investigation [30]. Based on that, it can be stated that the mechanism of action of eugenol against C. albicans is probably not related to the degradation of fungal cell wall.…”

“…Although several studies have investigated the antifungal effect of eugenol [14,[28][29][30], the mechanisms by which eugenol induces C. albicans cell death are not completely understood yet. In this study, the osmotic protective effect of sorbitol was not present, since there was no variation in the values of MIC, similarly to a previous investigation [30].…”

Efficacy of Pluchea dioscoridis leaf extract against pathogenic Candida albicans

“…Relatively little research concerned the mechanisms of their action, such as impact on the virulence factors [42,43]. This report includes results proving the influence of P. dioscoridis extract on possible mechanisms reported to be relevant for Candida pathogenesis, namely extracellular production of various enzymes.…”

Transformation of Eugenol and Safrole into Hydroxychavicol

“…1). Lewis acid is a commonly used reagent for demethylation, such as BBr 3 [8] and AlCl 3 [9], as well as for demethylenation, such as BF 3 O(C 2 H 5 ) 2 [10] and AlCl 3 [11][12]. Considerations used in determining reagent are availability and cost…”