ABSTRACT
Macromolecular chelators have potential applications in the medical area, for instance, in treatment of iron overload-related disorders and in the treatment of external infections. In this investigation, several novel iron(III)-selective hydroxypyridinone hexadentate-terminated first and second generation dendrimeric chelators were synthesized using a convergent strategy. Their iron chelating ability was demonstrated by UV/Visible spectrometry and high resolution mass spectrometry (HRMS). The iron binding affinities were also investigated by the competition with a fluorescent iron chelator CP691. The result indicated that these dendrimers possesses a high affinity for iron with a very high pFe3+ value, which is close to that of an isolated hexadentate unit. These dendrimeric chelators were found to exhibit inhibitory effect on the growth of both Gram-positive and Gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/pharmacology , Dendrimers/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Iron Chelating Agents/pharmacology , Pyridones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dendrimers/chemical synthesis , Dendrimers/chemistry , Dose-Response Relationship, Drug , Iron Chelating Agents/chemical synthesis , Iron Chelating Agents/chemistry , Microbial Sensitivity Tests , Molecular Structure , Pyridones/chemical synthesis , Pyridones/chemistry , Structure-Activity RelationshipABSTRACT
A range of hexadentate 3-hydroxypyridin-4-ones have been synthesized. These compounds were found to possess a high affinity for iron(III), with logK1 values of about 34 and pFe values over 30. Antimicrobial assays indicated that they can inhibit the growth of three clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) and three clinical isolates of Pseudomonas, suggesting that hexadentate 3-hydroxypyridin-4-ones have potential application in the treatment of wound infections.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Pseudomonas aeruginosa/drug effects , Pyridines/chemistry , Anti-Bacterial Agents/chemical synthesis , Chemistry Techniques, Synthetic , Drug Design , Drug Evaluation, Preclinical/methods , Iron/chemistry , Iron Chelating Agents/chemistry , Iron Chelating Agents/pharmacology , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A range of hydroxypyridinone-L-phenylalanine conjugates were synthesized starting from kojic acid. Their tyrosinase activity was determined, and it was found that one of the compounds ((S)-(5-(benzyloxy)-1-octyl-4-oxo-1,4-dihydropyridin-2-yl)methyl 2-amino-3-phenylpropanoate, 5e) showed potent inhibitory effect against mushroom tyrosinase, the IC50 values for monophenolase and diphenolase activities being 12.6 and 4.0 µM, respectively. It was also demonstrated that these conjugates are mixed-type inhibitors, suggesting they could bind to both the free enzyme and the enzyme-substrate complexes. MTT assay indicated that 5e was nontoxic to three cell lines. This compound may find applications in food preservation and cosmetics.
Subject(s)
Agaricales/enzymology , Enzyme Inhibitors/chemical synthesis , Fungal Proteins/antagonists & inhibitors , Monophenol Monooxygenase/antagonists & inhibitors , Phenylalanine/chemistry , Pyridones/chemistry , Agaricales/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Fungal Proteins/chemistry , Molecular Structure , Pyrones/chemistryABSTRACT
In the title mol-ecule, C(17)H(20)O(8), the two pyran rings form a dihedral angle of 61.2â (2)°. The two hy-droxy-methyl groups are each disordered over two sets of sites in a 0.764â (3):0.236â (3) ratio. In the crystal, O-Hâ¯O hydrogen bonds link the mol-ecules into layers parallel to the ac plane.
ABSTRACT
Iron is a critical element for the survival of bacteria. We have designed and synthesized two novel 3-hydroxypyridin-4-one hexadentate ligands with high affinity for iron(III), which disrupt bacterial iron absorption. Biological studies demonstrate that these two chelators have significant inhibitory effect against both Gram-positive and Gram-negative bacteria, and therefore have potential as antimicrobial agents.
