Nitrate Esters of Heteroaromatic Compounds as Candida albicans CYP51 Enzyme Inhibitors

Abstract

Four heteroaromatic compounds bearing nitrate esters were selected using a virtual-screening procedure as putative sterol 14α-demethylase (CYP51) Candida albicans inhibitors. Compounds were examined for their inhibition on C. albicans growth and biofilm formation as well as for their toxicity. NMR spectroscopy studies, in silico docking, and molecular dynamics simulations were used to investigate further the selectivity of these compounds to fungal CYP51. All compounds exhibited good antimicrobial properties, indicated with low minimal inhibitory concentrations and ability to inhibit formation of fungal biofilm. Moreover, all of the compounds had the ability to inhibit growth of C. albicans cells. N-(2-Nitrooxyethyl)-1Η-indole-2-carboxamide was the only compound with selectivity on C. albicans CYP51 that did not exhibit cytotoxic effect on cells isolated from liver and should be further investigated for selective application in new leads for the treatment of candidiasis.

Flavones, Flavonols, and Glycosylated Derivatives—Impact on Candida albicans Growth and Virulence, Expression of CDR1 and ERG11, Cytotoxicity

“…Potential of selected compounds to interfere with C. albicans 475/15 biofilm formation was investigated as previously described [39]. Briefly, C. albicans 475/15 was incubated with serial dilution of the compounds (MIC and subMICs) in YPD medium, in 96-well microtiter plates with adhesive bottom (Sarstedt, Nümbrecht, Germany), at 37 • C for 24 h. After incubation, wells were washed twice with sterile PBS and methanol was added into each well.…”

The Triazole Ring as a Privileged Scaffold for Putative Antifungals: Synthesis and Evaluation of a Series of New Analogues

“…Reference strains C. albicans ATCC 10231 and A. fumigates ATCC 9197 were also used in this study. Minimal inhibitory (MIC) and minimal fungicidal (MFC) concentrations were determined according to Smiljkovic et al [36] . The MIC values were considered as the lowest concentrations without microscopically observed fungal growth after 24 h incubation at 37 °C for Candida strains and 72 h at 28 °C for A. fumigatus .…”

“…Therefore, the MIC values of this strain were selected as the dependent variable for the QSAR models development. In the present study, the Multiple Linear Regression (MLR) analysis was implemented, using Canvas program, [36] to quantify the relationship between linear combinations of the dependent variable MIC and the statistical significance molecular descriptors. The validation of the derived QSAR models is necessary in order to identify and evaluate their predictive ability.…”

Novel Hit Compounds as Putative Antifungals: The Case of Aspergillus fumigatus

“…A time step of 2 fs was used, and all bonds were constrained using the LINCS algorithm. Lennard–Jones interactions were computed using a cutoff of 10 Å, and the electrostatic interactions were treated using PME with the same real-space cutoff as described before [51].…”