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1.
Eur J Med Chem ; 162: 51-58, 2019 Jan 15.
Article in English | MEDLINE | ID: mdl-30408748

ABSTRACT

There is an ongoing urgent need for new targeted antibacterial compounds with novel mechanisms of action for the treatment of infections caused by bacteria that are resistant to currently available materials. Since the expression of glycosidase enzymes within bacteria is unequally distributed, glycoside derivatives of antibacterial agents offer potential as targeted prodrugs for bacterial infections. Herein we report the synthesis and characterisation of four α-D-glycopyranosides and three ß-D-glycopyranosides of the broad antibacterial agent triclosan, in generally good synthetic yields, and with excellent purities. Each glycoside was analysed to determine its ability to inhibit the growth of a wide range of Gram-negative and Gram-positive organisms, including many of clinical significance. All of the triclosan glycosides that were synthesized demonstrated antibacterial activity against many of the organisms that were examined. For example, ß-galactoside (3a) and α-arabinoside (3c) had MIC values of 0.5 µg/ml for several strains of S. aureus and S. haemolyticus. The triclosan glycosides were also generally found to be more water soluble and much more selective than the underivatized triclosan, making them ideal both for the targeted inhibition of bacterial growth and as agents for the selective recovery of bacteria from mixed cultures. In the latter case, two Bacillus strains could be identified from various strains of Bacillus and Staphylococcus after inoculation onto Nutrient Agar No. 2 with 0.25 µg/ml triclosan-α-D-glucopyranoside (3e). This glucoside may, therefore, be of use for the isolation and identification of the food-poisoning organism Bacillus cereus.


Subject(s)
Anti-Bacterial Agents/pharmacology , Triclosan/analogs & derivatives , Anti-Bacterial Agents/chemical synthesis , Anti-Infective Agents, Local , Bacteria/drug effects , Bacterial Infections/drug therapy , Glucosides , Microbial Sensitivity Tests , Triclosan/chemical synthesis , Triclosan/pharmacology
2.
Bioorg Med Chem Lett ; 26(15): 3774-9, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27268308

ABSTRACT

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. ß-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.


Subject(s)
Aminoethylphosphonic Acid/pharmacology , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Glycosides/pharmacology , Aminoethylphosphonic Acid/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacteria/growth & development , Dose-Response Relationship, Drug , Glycosides/chemical synthesis , Glycosides/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
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