Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors

Daniela De Lucia; Oscar Méndez Lucio; Biagia Musio; Andreas Bender; Monika Listing; Sophie Dennhardt; Andreas Koeberle; Ulrike Garscha; Roberta Rizzo; Stefano Manfredini; Oliver Werz; Steven V Ley

doi:10.1016/j.ejmech.2015.07.011

Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors

Eur J Med Chem. 2015 Aug 28:101:573-83. doi: 10.1016/j.ejmech.2015.07.011. Epub 2015 Jul 15.

Authors

Affiliations

¹ 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: [email protected].
² Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: [email protected].
³ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: [email protected].
⁴ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: [email protected].
⁵ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: [email protected].
⁶ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: [email protected].
⁷ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: [email protected].
⁸ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: [email protected].
⁹ Department of Medical Sciences, University of Ferrara, Via Fossato di Mortara 74, 44100, Ferrara, Italy. Electronic address: [email protected].
¹⁰ Department of Life Sciences and Biotechnology, University of Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy. Electronic address: [email protected].
¹¹ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: [email protected].
¹² Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: [email protected].

PMID: 26197161
DOI: 10.1016/j.ejmech.2015.07.011

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.

Keywords: 5-Lipoxygenase inhibitor; Caffeic acid; Inflammation; Polyphenol; Triazole; Zileuton.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Arachidonate 5-Lipoxygenase / metabolism*
Caffeic Acids / chemical synthesis
Caffeic Acids / chemistry
Caffeic Acids / pharmacology*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Lipoxygenase Inhibitors / chemical synthesis*
Lipoxygenase Inhibitors / chemistry
Lipoxygenase Inhibitors / pharmacology*
Male
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology*
U937 Cells

Substances

Caffeic Acids
Lipoxygenase Inhibitors
Triazoles
Arachidonate 5-Lipoxygenase
caffeic acid