Síntese de potenciais agentes antifúngicos inibidores de glicosamina-6-fosfato síntase.

Abstract

The aminosugars are very important structural components of bacteria and fungi cell walls. Glucosamine-6-phosphate synthase (GlmS), which catalyses the first step of the aminosugar biosynthetic pathway i.e. the formation of D-glucosamine-6-phosphate from D-fructose-6-phosphate, is therefore an interesting target in the fight against microorganisms. In this work is described the synthesis of aromatics analogs of 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) and its epimer 2-amino-2-deoxy-D-manitol-6-phosphate (ADMP) two important inhibitors of GlmS: three phosphoramides and two phosphates; and a fluorine derivative of D-fructose-6-phosphate, the substrate of GlmS. The aromatics derivatives were obtained from the reaction of 3-nitrophenol or 3- benzoylresorcinol with racemic epichlorohydrine or the appropriately protected R and S terc-butyl 1,1- dimethyl-4-hydroxymethyl-2,2-dimethyl-3-oxazolidine carboxylate. For the fluorine derivative synthesis, the protected D-arabinose was the starting material and the reaction with diethyl difluoromethylthiophosphonate afforded the difluorinated D-fructose derivative which was deprotectedto give the derivative 1,1-difluoromethyl-D-fructose and was phosphorylated with hexokinase. None of the compounds showed antifungal activity against Aspergillus niger, Saccharomyces cerevisae,Candida albicans and Candida tropicallys, Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, Saccharomyces cerevisiae when evaluated using the agar diffusion method, in the concentration of 1 mg/mL. Antifungal activity of phosphates was evaluated by a serial dilution microplate method against Candida albicans, Candida krusei, Sacharomyces cerevisae and Escherichia coli. They showed no activity against the microorganismstested, until the concentration of 10 mg/mL. In the enzymatic assay against GlmS, the aromatic phosphates analogs displayed modest inhibitory activity, with IC50 in the mmol L-1 range.