title: Discovery of a novel dual fungal CYP51/human 5-lipoxygenase inhibitor: implications for anti-fungal therapy.
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.affiliation: Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Hoobler
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Andrew G S
authors.initials: AG
authors.lastname: Warrilow
authors.forename: Steven C
authors.initials: SC
authors.lastname: Perry
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Smyrniotis
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Josie E
authors.initials: JE
authors.lastname: Parker
authors.forename: Diane E
authors.initials: DE
authors.lastname: Kelly
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects*; D005658:Fungi / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D058886:Sterol 14-Demethylase / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D058886:Sterol 14-Demethylase