title: Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors.
abstract: In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization.
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: daniela.delucia@unife.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Lucia
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: om268@cam.ac.uk.
authors.forename: Oscar Méndez
authors.initials: OM
authors.lastname: Lucio
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: bm450@cam.ac.uk.
authors.forename: Biagia
authors.initials: B
authors.lastname: Musio
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: ab454@cam.ac.uk.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Monika.Listing@uni-jena.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Listing
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Sophie.Dennhardt@uni-jena.de.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dennhardt
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Andreas.Koeberle@uni-jena.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Ulrike.Garscha@uni-jena.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
authors.affiliation: Department of Medical Sciences, University of Ferrara, Via Fossato di Mortara 74, 44100, Ferrara, Italy. Electronic address: roberta.rizzo@unife.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rizzo
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy. Electronic address: stefano.manfredini@unife.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Manfredini
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Oliver.Werz@uni-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: svl1000@cam.ac.uk.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
mesh_terms: D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D002109:Caffeic Acids; D016859:Lipoxygenase Inhibitors; D014230:Triazoles; D001094:Arachidonate 5-Lipoxygenase; C040048:caffeic acid
keywords: 5-Lipoxygenase inhibitor; Caffeic acid; Inflammation; Polyphenol; Triazole; Zileuton