Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1-hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents.
Several novel chelators based on 1-hydroxy-2(1H)-pyridinone coordinating groups decorating a triaza macrocyclic backbone scaffold were synthesised as potential powerful Fe(3+) chelators capable of competing with bacterial siderophores. In particular, a novel chloromethyl derivative of 1-hydroxy-2(1H)-pyridinone exploiting a novel protective group for this family of coordinating groups was developed. These are the first examples of hexadentate chelators based on 1-hydroxy-2(1H)-pyridinone to be shown to have a biostatic activity against a range of pathogenic bacteria. Their efficacy as biostatic agents was assessed revealing that minor variations in the structure of the chelator can affect efficacy profoundly. The minimal inhibitory concentrations of our best tested novel chelators approach or are comparable to those for 1,4,7-tris(3-hydroxy-6-methyl-2-pyridylmethyl)-1,4,7-triazacyclononane, the best Fe(3+) chelator known to date. The retarding effect these chelators have on microbial growth suggests that they could have a potential application as a co-active alongside antibiotics in the fight against infections.
Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom.
David G
DG
Workman
Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom.
Michael
M
Hunter
Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom.
Lynn G
LG
Dover
Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom. Electronic address: david.tetard@northumbria.ac.uk.
David
D
Tétard
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D015195:Drug Design; D004758:Enterobactin / Q000737:chemistry; D005663:Furans / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry; D011073:Polyamines / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D005663:Furans; D006571:Heterocyclic Compounds; D007502:Iron Chelating Agents; D009842:Oligopeptides; D011073:Polyamines; D011728:Pyridones; D012997:Solvents; C430721:bacillibactin; C005391:diethylenetriamine; D004758:Enterobactin; C018674:tetrahydrofuran; C075712:1,4,7-triazacyclononane; D007501:Iron; C546958:1-hydroxy-2(1H)-pyridinone
1-Hydroxy-2(1H)-pyridinone; Bacterial growth; Biostatic agent; Chelator; Siderophore