title: 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).
abstract: In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey. Electronic address: banoglu@gazi.edu.tr.
authors.forename: Erden
authors.initials: E
authors.lastname: Banoglu
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey.
authors.forename: Erşan
authors.initials: E
authors.lastname: Çelikoğlu
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Völker
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey.
authors.forename: Abdurrahman
authors.initials: A
authors.lastname: Olgaç
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Gerstmeier
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey.
authors.forename: Burcu
authors.initials: B
authors.lastname: Çalışkan
authors.affiliation: Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany; Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743, Jena, Germany.
authors.forename: Ulrich S
authors.initials: US
authors.lastname: Schubert
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D008958:Models, Molecular; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D007555:Isoxazoles; D015289:Leukotrienes
keywords: 5-lipoxygenase; 5-lipoxygenase-activating protein; Inflammation; Isoxazole; Leukotrienes