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.
Highlights
Natural products have been regarded as rich sources of potential chemotherapeutic agents
Due to high minimum inhibitory concentrations, most of them are often overlooked, which results in a decline of investment in this area, despite the fact that natural products are a source of new drugs [1]
RNA extraction and gene expressions of ERG11 gene in C. albicans ATCC90028, FLC- susceptible C. albicans 2281 and FLC- resistant C. albicans 3001 cells when exposed to Minimum inhibitory concentration (MIC) values of the test compounds E1-E6 or FLC were done as described previously [26]
Summary
Natural products have been regarded as rich sources of potential chemotherapeutic agents. In antifungal chemotherapy the heterocyclic compounds “azoles” have been immensely researched and currently these are the most popular class of antifungals used in medicine These compounds bind as the sixth ligand to the heme group in CYP51, changing the structure of the active site and acting as non-competitive inhibitors [4]. A novel strategy of generating an effective treatment option is the combined use of the semi-synthetic analogues, with enhanced potency, compared to the precursor natural product and an already established drug [13,14]. The mechanism of action was elucidated by quantifying the ergosterol content in different Candida isolates following treatment with semi-synthetic eugenol derivatives and the results were validated by docking studies. The differences in the ergosterol biosynthesis are attributed to the differences in the gene expression patterns and in view of this; real time-PCR (qRT-PCR) of one of the striking gene of ergosterol biosynthesis (ERG11) was included in the study
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