title: 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 OCH(3) at C-2 or the presence of one or two NO(2) 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.
authors.affiliation: Departamento de Ciencias Químicas, Universidad Andrés Bello, Campus Viña del Mar, Los Fresnos N° 52, Viña del Mar 2520000, Chile. hcarrasco@unab.cl
authors.forename: Héctor
authors.initials: H
authors.lastname: Carrasco
authors.forename: Marcela
authors.initials: M
authors.lastname: Raimondi
authors.forename: Laura
authors.initials: L
authors.lastname: Svetaz
authors.forename: Melina
authors.initials: M
authors.lastname: Di Liberto
authors.forename: María V
authors.initials: MV
authors.lastname: Rodriguez
authors.forename: Luis
authors.initials: L
authors.lastname: Espinoza
authors.forename: Alejandro
authors.initials: A
authors.lastname: Madrid
authors.forename: Susana
authors.initials: S
authors.lastname: Zacchino
mesh_terms: D000107:Acetylation; D003883:Arthrodermataceae / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification; D002177:Candidiasis / Q000382:microbiology; D002462:Cell Membrane / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D004347:Drug Interactions; D004875:Ergosterol / Q000494:pharmacology; D005054:Eugenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D012451:Safrole / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014005:Tinea / Q000382:microbiology; D014249:Trichophyton / Q000187:drug effects / Q000302:isolation & purification
chemical_list: D005054:Eugenol; D012451:Safrole; D004875:Ergosterol