Discovery of a novel dual fungal CYP51/human 5-lipoxygenase inhibitor: implications for anti-fungal therapy.

Therapeutic Approaches
Medicinal Chemistry

Abstract

We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component.

Authors

Hoobler, Eric K; Rai Bantukallu, Ganesha; Warrilow, Andrew G S; Perry, Steven C; Smyrniotis, Christopher J; Jadhav, Ajit; Simeonov, Anton; Parker, Josie E; Kelly, Diane E; Maloney, David J; Kelly, S L; Holman, Theodore R;

Keywords

  • Antifungal Agents/ pharmacology
  • Arachidonate 5-Lipoxygenase/ drug effects
  • Fungi/ enzymology
  • Humans
  • Inhibitory Concentration 50
  • Leukotriene B4/ antagonists & inhibitors
  • Lipoxygenase Inhibitors/ pharmacology
  • Sterol 14-Demethylase/ drug effects

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