title: Synergistic Interactions of Eugenol-tosylate and Its Congeners with Fluconazole against Candida albicans.
abstract: We previously reported the antifungal properties of a monoterpene phenol "Eugenol" against different Candida strains and have observed that the addition of methyl group to eugenol drastically increased its antimicrobial potency. Based on the results and the importance of medicinal synthetic chemistry, we synthesized eugenol-tosylate and its congeners (E1-E6) and tested their antifungal activity against different clinical fluconazole (FLC)- susceptible and FLC- resistant C. albicans isolates alone and in combination with FLC by determining fractional inhibitory concentration indices (FICIs) and isobolograms calculated from microdilution assays. Minimum inhibitory concentration (MIC) results confirmed that all the tested C. albicans strains were variably susceptible to the semi-synthetic derivatives E1-E6, with MIC values ranging from 1-62 μg/ml. The test compounds in combination with FLC exhibited either synergy (36%), additive (41%) or indifferent (23%) interactions, however, no antagonistic interactions were observed. The MICs of FLC decreased 2-9 fold when used in combination with the test compounds. Like their precursor eugenol, all the derivatives showed significant impairment of ergosterol biosynthesis in all C. albicans strains coupled with down regulation of the important ergosterol biosynthesis pathway gene-ERG11. The results were further validated by docking studies, which revealed that the inhibitors snugly fitting the active site of the target enzyme, mimicking fluconazole, may well explain their excellent inhibitory activity. Our results suggest that these compounds have a great potential as antifungals, which can be used as chemosensitizing agents with the known antifungal drugs.
authors.affiliation: Department of Oral Biological Sciences, School of Oral Health Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, South Africa.
authors.forename: Aijaz
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Departmento de Quimica, FCTUC, Universidade de Coimbra, Rua Larga, Coimbra, Portugal.
authors.forename: Mohmmad Younus
authors.initials: MY
authors.lastname: Wani
authors.affiliation: Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, South Africa.
authors.forename: Amber
authors.initials: A
authors.lastname: Khan
authors.affiliation: College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Munawarah, KSA.|Department of Biosciences, Jamia Millia Islamia, New Delhi, Delhi, India.
authors.forename: Nikhat
authors.initials: N
authors.lastname: Manzoor
authors.affiliation: Department of Oral Biological Sciences, School of Oral Health Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, South Africa.
authors.forename: Julitha
authors.initials: J
authors.lastname: Molepo
mesh_terms: D002176:Candida albicans / Q000254:growth & development*; D002177:Candidiasis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005054:Eugenol / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015725:Fluconazole / Q000819:agonists / Q000494:pharmacology*
chemical_list: D005054:Eugenol; D015725:Fluconazole