Synthesis of 4-phenoxybenzamide adenine dinucleotide as NAD analogue with inhibitory activity against enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis

Laurent Bonnac, Guang Yao Gao, Liqiang Chen, Krzysztof Felczak, Eric M. Bennett, Hua Xu, Tae Soo Kim, Nina Liu, Hye Won Oh, Peter J. Tonge, Krzysztof W Pankiewicz

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The chemical synthesis of 4-phenoxybenzamide adenine dinucleotide (3), a NAD analogue which mimics isoniazid-NAD adduct and inhibits Mycobacterium tuberculosis NAD-dependent enoyl-ACP reductase (InhA), is reported. The 4-phenoxy benzamide riboside (1) has been prepared as a key intermediate, converted into its 5′-mononucleotide (2), and coupled with AMP imidazolide to give the desired NAD analogue 3. It inhibits InhA with IC50 = 27 μM.

Original languageEnglish (US)
Pages (from-to)4588-4591
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number16
DOIs
StatePublished - Aug 15 2007

Bibliographical note

Funding Information:
These studies were funded by the Center for Drug Design, University of Minnesota. We thank the Minnesota Supercomputing Institute for computer time.

Keywords

  • Enoyl-ACP reductase (InhA)
  • Fragment-based drug discovery
  • Isoniazid
  • M. tuberculosis
  • NAD analogues

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