Synthesis and biological study of deoxy glycosides with potential antimicrobial activity against Bacillus spp.

Tese de mestrado em Química, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2011In previous work, a series of 2,6-dideoxy glycosides have demonstrated antibacterial potential mainly against Bacillus species, Enterococcus faecalis and Listeria monocytogenes. The present research is directed towards the synthesis of new 2,6-dideoxy glycosides and analogs, in order to build a small library of compounds providing novel structure-activity relationships, aiming to understand the mode of action of such compounds. In a parallel pathway, the study of the biological effect of such compounds and the induced metabolic changes will ultimately allow a target-guided synthesis, where the converging pathways will meet to give a novel class of antibiotics. The first steps were given using a phenotypic approach to further understand the changes in the bacterial metabolism induced by this type of compounds. Meanwhile, the synthesis of novel derivatives using the most active compound as scaffold was performed, and the assessment of their antibacterial capacity provided new data for a solid structure-activity relationship study. In this work we present a synthetic strategy for 2,6-dideoxy glycosides based on reaction of 6-deoxyglycals with a variety of alcohols catalysed by triphenylphosphane hydrobromide. The antibacterial activity exhibited by these new compounds was evaluated by agar dilution plates and microdilution methods. In addition, a phenotypic microarray assay was also performed, in order to further understand the biological effects of the synthesized compounds over Bacillus cereus. The first results obtained suggest that the mechanism of action is associated with the cell membrane or its components, confirming dodecyl 2,6-dideoxy-α-L-arabino-hexopyranoside as the compound with the best antimicrobial activity over B. cereus strains. Once the rise of bacterial resistance is a real problem of public health, the demand for new antibiotics with new mechanisms of action is growing, to which the present research intends to answer