Synthesis and structure-function analysis of Fe(II)-form-selective antibacterial inhibitors of Escherichia coli methionine aminopeptidase

Wen Long Wang, Sergio C. Chai, Qizhuang Ye

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Methionine aminopeptidase (MetAP) is a promising target for the development of novel antibacterial, antifungal and anticancer therapy. Based on our previous results, catechol derivatives coupled with a thiazole or thiophene moiety showed high potency and selectivity toward the Fe(II)-form of Escherichia coli MetAP, and some of them clearly showed antibacterial activity, indicating that Fe(II) is likely the physiologically relevant metal for MetAP in E. coli and other bacterial cells. To further understand the structure-function relationship of these Fe(II)-form selective MetAP inhibitors, a series of catechol derivatives was designed and synthesized by replacement of the thiazole or thiophene moiety with different five-membered and six-membered heterocycles. Inhibitory activities of these newly synthesized MetAP inhibitors indicate that many five- and six-membered rings can be accommodated by MetAP and potency on the Fe(II)-form can be improved by introducing substitutions on the heterocyles to explore additional interactions with the enzyme. The furan-containing catechols 11-13 showed the highest potency at 1 μM on the Fe(II)-form MetAP, and they were also among the best inhibitors for growth inhibition against E. coli AS19 strain. These findings provide useful information for the design and discovery of more effective MetAP inhibitors for therapeutic applications.

Original languageEnglish
Pages (from-to)1080-1083
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number4
DOIs
StatePublished - Feb 15 2009

Fingerprint

Aminopeptidases
Methionine
Escherichia coli
Thiazoles
Thiophenes
Catechols
Derivatives
Growth Inhibitors
Substitution reactions
Metals
Enzymes
Therapeutics

Keywords

  • Antibacterial
  • Catechol
  • Drug discovery
  • Metalloform
  • Methionine aminopeptidase
  • Protease

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Synthesis and structure-function analysis of Fe(II)-form-selective antibacterial inhibitors of Escherichia coli methionine aminopeptidase. / Wang, Wen Long; Chai, Sergio C.; Ye, Qizhuang.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 4, 15.02.2009, p. 1080-1083.

Research output: Contribution to journalArticle

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