Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors

Maria Giovanna Chini; Rosa De Simone; Ines Bruno; Raffaele Riccio; Friederike Dehm; Christina Weinigel; Dagmar Barz; Oliver Werz; Giuseppe Bifulco

doi:10.1016/j.ejmech.2012.05.014

Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors

Eur J Med Chem. 2012 Aug:54:311-23. doi: 10.1016/j.ejmech.2012.05.014. Epub 2012 May 18.

Authors

Maria Giovanna Chini¹, Rosa De Simone, Ines Bruno, Raffaele Riccio, Friederike Dehm, Christina Weinigel, Dagmar Barz, Oliver Werz, Giuseppe Bifulco

Affiliation

¹ Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.

PMID: 22683242
DOI: 10.1016/j.ejmech.2012.05.014

Abstract

Microsomal prostaglandin E(2) synthase (mPGES)-1 and 5-lipoxygenase (5-LO) are pivotal enzymes in the biosynthesis of the pro-inflammatory PGE(2) and leukotrienes, respectively. The design and synthesis of a second series of mPGES-1 inhibitors based on a triazole scaffold are described. Our studies allowed us to draw a tentative SAR profile and to optimize this series with the identification of compounds 10, 11 and 14-15 which displayed potent mPGES-1 inhibition in a cell-free assay. In addition, compounds 5, 10, 12 and 14-16 also blocked 5-LO activity in cell-free and cell-based test systems, emerging as very promising candidates for the development of safer and more effective anti-inflammatory drugs.

Publication types

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

MeSH terms

Adult
Arachidonate 5-Lipoxygenase / chemistry
Arachidonate 5-Lipoxygenase / metabolism*
Cell Line, Tumor
Chemistry Techniques, Synthetic
Drug Design*
Humans
Inhibitory Concentration 50
Intramolecular Oxidoreductases / antagonists & inhibitors*
Intramolecular Oxidoreductases / chemistry
Intramolecular Oxidoreductases / metabolism
Ligands
Lipoxygenase Inhibitors / chemical synthesis*
Lipoxygenase Inhibitors / chemistry
Lipoxygenase Inhibitors / metabolism
Lipoxygenase Inhibitors / pharmacology*
Molecular Docking Simulation
Prostaglandin-E Synthases
Protein Conformation
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / metabolism
Triazoles / pharmacology*

Substances

Ligands
Lipoxygenase Inhibitors
Triazoles
Arachidonate 5-Lipoxygenase
Intramolecular Oxidoreductases
PTGES protein, human
Prostaglandin-E Synthases