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.
- 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].
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.