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Tuning the bioactivity of tensioactive deoxy glycosides to structure: antibacterial activity versus selective cholinesterase inhibition rationalized by molecular docking
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Advisor(s)
Abstract(s)
New octyl/dodecyl 2,6-dideoxy-D-arabino-hexopyranosides
have been synthesized by a simple but efficient methodology
based on the reaction of glycals with alcohols catalysed by
triphenylphosphane hydrobromide, deprotection, regioselective tosylation and reduction. Their surface-active properties
were evaluated in terms of adsorption and aggregation parameters and compared with those of 2-deoxy-D-glycosides
and 2,6-dideoxy-L-glycosides. Deoxygenation at the 6-position led to a decrease in the critical micelle concentration,
and an increase in the adsorption efficiency (pC20) promoting
aggregation more efficiently than adsorption. With regard to
the antibacterial activity, dodecyl 2,6-dideoxy-α-L-arabino-hexopyranoside was the most active compound towards Bacillus anthracis (MIC 25 μM), whereas its enantiomer exhibited a MIC value of 50 μM. Both 2,6-dideoxy glycosides were
active towards Bacillus cereus, Bacillus subtilis, Enterococcus
faecalis and Listeria monocytogenes. In contrast, none of the
2-deoxy glycosides was significantly active. These results
and the data on surface activity suggest that aggregation is
a key issue for antimicrobial activity. Beyond infection, Alzheimer’s disease also threatens elderly populations. In the search for butyrylcholinesterase (BChE) selective inhibition, 2-
deoxy glycosides were screened in vitro by using Ellman’s
assay. Octyl 2-deoxy-α-D-glycoside was found to be a BChE
selective inhibitor promoting competitive inhibition. Docking
studies supported these results as they pinpoint the importance of the primary OH group in stabilizing the BChE inhibitor complex. A size-exclusion mechanism for inhibition has
been proposed based on the fact that acetylcholinesterase
(AChE) exhibits several bulky residues that hinder access to
the active-site cavity. This work shows how the deoxygenation pattern, configuration and functionality of the anomeric
centre can tune physical and surface properties as well as
the bioactivity of these multifunctional and stereochemically
rich molecules.
Description
Keywords
Synthetic methods Medicinal chemistry Glycosides Surfactants Biological activity Molecular docking Métodos de síntese Aplicação em medicina Glicosídeos Surfactantes Actividade biológica Ancoragem molecular
Citation
Martins, A.; Santos, M.S.; Dias, C.; Serra, P.; Cachatra, V.; Pais, J.; Caio, J.; Teixeira, V.H.; Machuqueiro, M.; Silva, M.S.; Pelerito, A.; Justino, J.; Goulart, M.; Silva, F.V. and Rauter, A.P. (2013), Tuning the bioactivity of tensioactive deoxy glycosides to structure: antibacterial activity versus selective cholinesterase inhibition rationalized by molecular docking. European Journal of Organic Chemistry, 2013, 1448-1459. https://doi.org/10.1002/ejoc.201201520
Publisher
Wiley