Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
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Authors: | Eric K. Hoobler Ganesha Rai Andrew G. S. Warrilow Steven C. Perry Christopher J. Smyrniotis Ajit Jadhav Anton Simeonov Josie E. Parker Diane E. Kelly David J. Maloney S. L. Kelly Theodore R. Holman |
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Affiliation: | 1. Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, United States of America.; 2. NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Bethesda, Maryland, United States of America.; 3. Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom.; Southern Illinois University School of Medicine, United States of America, |
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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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