Synthesis and biological analysis of novel glycoside derivatives of l-AEP, as targeted antibacterial agents.
To develop targeted methods for treating bacterial infections, the feasibility of using glycoside derivatives of the antibacterial compound l-R-aminoethylphosphonic acid (l-AEP) has been investigated. These derivatives are hypothesized to be taken up by bacterial cells via carbohydrate uptake mechanisms, and then hydrolyzed in situ by bacterial borne glycosidase enzymes, to selectively afford l-AEP. Therefore the synthesis and analysis of ten glycoside derivatives of l-AEP, for selective targeting of specific bacteria, is reported. The ability of these derivatives to inhibit the growth of a panel of Gram-negative bacteria in two different media is discussed. β-Glycosides (12a) and (12b) that contained l-AEP linked to glucose or galactose via a carbamate linkage inhibited growth of a range of organisms with the best MICs being <0.75mg/ml; for most species the inhibition was closely related to the hydrolysis of the equivalent chromogenic glycosides. This suggests that for (12a) and (12b), release of l-AEP was indeed dependent upon the presence of the respective glycosidase enzyme.
Thermofisher Scientific, Wade Road, Basingstoke, Hampshire RG24 8PW, UK.
Richard
R
Bovill
Reading School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK.
Philip G
PG
Evans
Reading School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK.
Gemma L
GL
Howse
Reading School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK.
Helen M I
HM
Osborn
D000615:Aminoethylphosphonic Acid / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006027:Glycosides; D000615:Aminoethylphosphonic Acid
Antibacterial; Glycosidase; Glycoside; Prodrug