Hexadentate 3-hydroxypyridin-4-ones with high iron(III) affinity: Design, synthesis and inhibition on methicillin resistant Staphylococcus aureus and Pseudomonas strains

Zhou, Ying Jun; Liu, Mu Song; Rugaie, Osamah Al; Kong, Xiaole; Alsam, Selwa; Battah, Sinan; Xie, Yuan; Hider, Robert C.; Zhou, Tao

doi:10.1016/j.ejmech.2015.02.050

Cited by 38 publications

(30 citation statements)

References 31 publications

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“…A significant number of reports have also described growth inhibition of a range of pathogenic bacteria by bidentate or hexadentate chelators based upon 3.4-HOPO [34][35][36][37][38][39][40][41][42][43]. To achieve high pFe 3+ , hexadentate chelators are preferred to bidentate ones, especially since their mode of action as biostatic agents is expected to be extracellular and therefore do not suffer from size restriction to penetrate the microbes.…”

Section: Introductionmentioning

confidence: 99%

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

Workman

Hunter

Dover

et al. 2016

Journal of Inorganic Biochemistry

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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.

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Section: Introductionmentioning

confidence: 99%

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

Workman

Hunter

Dover

et al. 2016

Journal of Inorganic Biochemistry

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“…[83,84] Da es bei extrazellulärw irkenden antimikrobiellen Metallchelatoren keine Grçßenbeschränkungen gibt, ist die hçhere thermodynamische und kinetische eine hçhere Affinitätf ürF e 3+ und eine hçhere antimikrobielle Aktivitäta ls Diethylentriaminpentaessigsäure (DTPA, 51) [84,85] (Abbildung 15), und ihre Fe 3+ -Komplexe werden von E. coli oder S. aureus nicht aufgenommen. [86,87] Obwohl 1,2-HOPOs schwächere Fe 3+ -koordinierende Gruppen enthalten, zeigten einige doch antimikrobielle Eigenschaften. [86,87] Obwohl 1,2-HOPOs schwächere Fe 3+ -koordinierende Gruppen enthalten, zeigten einige doch antimikrobielle Eigenschaften.…”

Section: Angewandte Chemieunclassified

“…[165,166] Um alle Eisenaufnahmesysteme von uropathogenen E. coli (UPEC) außer Kraft zu setzen, wurde ein wachstumsbasierter Te st mit ganzen Zellen unter Eisenmangelbedingungen durchgeführt, mit einem Te st unter normalen Kultivierungsbedingungen zur Kontrolle.1 6S ubstanzen aus einer Bibliothek von etwa 150 000 Substanzen zeigten spezifische Hemmwirkungen unter Eisenmangelbedingungen mit IC 50 -Werten im Bereich von 0.8-48 mm.U ntersuchungen zum Wirkmechanismus mit Mutanten, in denen einzelne Funktionen ausgeschaltet waren, zeigten, dass fürwenigstens zwei Substanzen vermutlich das TonB-System das Target ist (86,87;Abbildung 27). Die bençtigte Energie stammt aus der protonenmotorischen Kraft der inneren bakteriellen Membran und wird über das TonB-Proteinsystem an den Siderophor-Rezeptor geliefert (Abbildung 1).…”

Section: Siderophortransport In Die Zelleunclassified

“…[ [81,82] Auch die Hydroxypyridinone (HOPOs) 44-46 erfüllen diese Anforderung und haben daher das Interesse als alternative eisenbindende Einheiten geweckt (Abbildung 13). [81,[83][84][85][86][87][88] In ihrer deprotonierten Form stellen diese Liganden benachbarte Sauerstoffdonoren bereit, die fünfgliedrige Chelatringe bilden kçnnen und thermodynamisch mit den chelatisierenden Einheiten der natürlichen Siderophore konkurrieren kçnnen, z. B. Catecholat-, Hydroxamat-und Hydroxycarboxylat-Gruppen.…”

Section: Angewandte Chemieunclassified

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Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

et al. 2017

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Eine der Verteidigungsstrategien eines Wirtes gegen bakterielle Infektionen ist der Entzug essentieller Metallionen, insbesondere von Eisenionen, durch Komplexierung. Dies wird als Nährstoffimmunität (“nutritional immunity”) bezeichnet. Bakterien haben jedoch Strategien zur Anpassung an den Eisenmangel entwickelt. Sie “stehlen” zum Beispiel Eisen vom Wirt oder von anderen Bakterien durch spezifische Chelatoren mit einer hohen Affinität für Eisen. Die komplexen Wechselwirkungen zwischen Wirt und Pathogen zur Homöostase von Metallionen bieten zahlreiche Angriffspunkte für die Entwicklung neuer antibakterieller Wirkstoffe. Dieser Aufsatz ist auf Prozesse mit Eisenbeteiligung fokussiert. Es werden die neuesten Entwicklungen und mögliche Perspektiven für die Entwicklung von Antibiotikaresistenzen diskutiert.

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“…7 HOPO compounds have also been evaluated for cancer treatment 8 and as novel antibacterial compounds. 9,10 HOPO siderophores have been studied in a variety of diagnostic applications including as MRI contrast agents 11,12 and in positron emission tomography (PET). 13,14 It is important to mention that hydroxypyridinones for selective actinide binding and remediation of transuranic waste is an active area of interest.…”

Section: Introductionmentioning

confidence: 99%

Preparation of 3-benzyloxy-2-pyridinone functional linkers: tools for the synthesis of 3,2-hydroxypyridinone (HOPO) and HOPO/hydroxamic acid chelators

et al. 2015

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In contrast to 2,3-dihydroxypyridine, the 3-benzyloxy protected derivative, 2, undergoes facile alkylation at ambient temperatures with a variety of functionalized alkyl halides in good yields. This alkylation has been used to prepare a number of linkers that permit the attachment of 3,2-HOPO moieties onto various scaffolds using a wide range of coupling methods. The Mitsunobu reaction of 2 with representative alcohols was found to be of limited value due to competing O-alkylation that led to product mixtures. The phthalimide 3j can be converted in two steps to HOPO isocyanate 6 in excellent yields. Isocyanate 6 can be coupled to amines at room temperature or to alcohols in refluxing dichloroethane to obtain the corresponding urea or carbamate linked ligand systems. The coupling of isocyanate 6 with TREN followed by deprotection gave the tris-HOPO 10, an interesting target as it has both cationic and anionic binding sites. The HOPO hydroxylamine linker 11 was shown to be especially valuable as its coupling with carboxylic acids proceeds with the concomitant generation of an additional hydroxamate ligand moiety in the framework. The utility of this linker was shown by the preparation of two mixed HOPO-hydroxamate chelators, 16 and 19, based on the structure of desferrioxamine, a well-known trihydroxamate siderophore.

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Hexadentate 3-hydroxypyridin-4-ones with high iron(III) affinity: Design, synthesis and inhibition on methicillin resistant Staphylococcus aureus and Pseudomonas strains

Cited by 38 publications

References 31 publications

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

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

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

Preparation of 3-benzyloxy-2-pyridinone functional linkers: tools for the synthesis of 3,2-hydroxypyridinone (HOPO) and HOPO/hydroxamic acid chelators

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