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.

Daniela De Lucia ¹, Oscar Méndez Lucio ², Biagia Musio ³, Andreas Bender ⁴, Monika Listing ⁵, Sophie Dennhardt ⁶, Andreas Koeberle ⁷, Ulrike Garscha ⁸, Roberta Rizzo ⁹, Stefano Manfredini ¹⁰, Oliver Werz ¹¹, Steven V Ley ¹²

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: daniela.delucia@unife.it.
2 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: om268@cam.ac.uk.
3 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: bm450@cam.ac.uk.
4 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: ab454@cam.ac.uk.
5 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Monika.Listing@uni-jena.de.
6 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Sophie.Dennhardt@uni-jena.de.
7 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Andreas.Koeberle@uni-jena.de.
8 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Ulrike.Garscha@uni-jena.de.
9 Department of Medical Sciences, University of Ferrara, Via Fossato di Mortara 74, 44100, Ferrara, Italy. Electronic address: roberta.rizzo@unife.it.
10 Department of Life Sciences and Biotechnology, University of Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy. Electronic address: stefano.manfredini@unife.it.
11 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: Oliver.Werz@uni-jena.de.
12 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: svl1000@cam.ac.uk.

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.

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