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 14a-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)-1Hindole- 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.This work was supported financially by the Serbian Ministry of Education, Science, and Technological Development (Grant number 173032). Binding studies to CaCYP51 were supported by the Slovenian Research Agency (Grants P1-0010 and J1-8145) and by a program of scientific and technological cooperation between the Republic of Serbia and the Republic of Slovenia “A combined methodology towards the development of novel, selective inhibitors of Candida CYP51”.info:eu-repo/semantics/publishedVersio