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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 Orcid Logo, Diane Kelly, David J Maloney, Steven Kelly Orcid Logo, Theodore R Holman

PLoS ONE, Volume: 8, Issue: 6

Swansea University Authors: Andrew Warrilow, Josie Parker Orcid Logo, Diane Kelly, Steven Kelly Orcid Logo

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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 pheny...

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Published in: PLoS ONE
ISSN: 1932-6203
Published: 2013
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URI: https://cronfa.swan.ac.uk/Record/cronfa15178
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spelling 2021-10-26T16:57:21.1794016 v2 15178 2013-07-08 Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy f066e233e8d0136c9f547b86fa43747f Andrew Warrilow Andrew Warrilow true false e563ed4e1c7db8d1e131fb78a5f8d0d5 0000-0002-3855-4194 Josie Parker Josie Parker true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2013-07-08 FGMHL 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 Journal Article PLoS ONE 8 6 1932-6203 31 12 2013 2013-12-31 10.1371/journal.pone.0065928 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2021-10-26T16:57:21.1794016 2013-07-08T14:05:36.6335867 Swansea University Medical School Medicine Daotai Nie 1 Eric K Hoobler 2 Ganesha Rai 3 Andrew Warrilow 4 Steven C Perry 5 Christopher J Smyrniotis 6 Ajit Jadhav 7 Anton Simeonov 8 Josie Parker 0000-0002-3855-4194 9 Diane Kelly 10 David J Maloney 11 Steven Kelly 0000-0001-7991-5040 12 Theodore R Holman 13
title Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
spellingShingle Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
Andrew Warrilow
Josie Parker
Diane Kelly
Steven Kelly
title_short Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
title_full Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
title_fullStr Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
title_full_unstemmed Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
title_sort Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
author_id_str_mv f066e233e8d0136c9f547b86fa43747f
e563ed4e1c7db8d1e131fb78a5f8d0d5
5ccf81e5d5beedf32ef8d7c3d7ac6c8c
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow
e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Andrew Warrilow
Josie Parker
Diane Kelly
Steven Kelly
author2 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
format Journal article
container_title PLoS ONE
container_volume 8
container_issue 6
publishDate 2013
institution Swansea University
issn 1932-6203
doi_str_mv 10.1371/journal.pone.0065928
college_str Swansea University Medical School
hierarchytype
hierarchy_top_id swanseauniversitymedicalschool
hierarchy_top_title Swansea University Medical School
hierarchy_parent_id swanseauniversitymedicalschool
hierarchy_parent_title Swansea University Medical School
department_str Medicine{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Medicine
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description 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
published_date 2013-12-31T03:24:45Z
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