Structure-based redesign of an edema toxin inhibitor

Deliang Chen, Lili Ma, John J. Kanalas, Jian Gao, Jennifer Pawlik, Maria Estrella Jimenez, Mary A. Walter, Johnny W. Peterson, Scott R. Gilbertson, Catherine H. Schein

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3′,5′-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15 μg/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure-activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria.

Original languageEnglish (US)
Pages (from-to)368-376
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number1
StatePublished - Jan 1 2012
Externally publishedYes


  • Adenylyl cyclase toxin inhibitor
  • Anthrax
  • Cell-based assay
  • Computer aided design
  • ETEC (enterotoxigenic E. coli)
  • Non-nucleotide inhibitors
  • Toxicity profiling

ASJC Scopus subject areas

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


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