Journal article 1338 views
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
Daotai Nie,
Eric K Hoobler,
Ganesha Rai,
Andrew Warrilow,
Steven C Perry,
Christopher J Smyrniotis,
Ajit Jadhav,
Anton Simeonov,
Josie Parker,
Diane Kelly,
David J Maloney,
Steven Kelly 
,
Theodore R Holman
,
Theodore R Holman
PLoS ONE, Volume: 8, Issue: 6
Swansea University Authors:
Andrew Warrilow, Josie Parker, Diane Kelly, Steven Kelly
Full text not available from this repository: check for access using links below.
DOI (Published version): 10.1371/journal.pone.0065928
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 pheny...
| Published in: | PLoS ONE |
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| ISSN: | 1932-6203 |
| Published: |
2013
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa15178 |
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| 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 |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Issue: |
6 |