Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Iyas Aldib, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Michel Gelbcke, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Jalal Soubhye, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Martine Prévost, Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Paul G Furtmüller, Department of Chemistry, Division of Biochemistry at the Vienna Institute of BioTechnology, BOKU-University of Natural Resources and Life Sciences, Muthgasse 18, A-1190, Vienna, Austria.
  • ,
  • Christian Obinger, Department of Chemistry, Division of Biochemistry at the Vienna Institute of BioTechnology, BOKU-University of Natural Resources and Life Sciences, Muthgasse 18, A-1190, Vienna, Austria.
  • ,
  • Betina Elfving
  • Ibaa Chikh Alard, Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • ,
  • Goedele Roos, Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Cédric Delporte, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Gilles Berger, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Damien Dufour, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Karim Zouaoui Boudjeltia, Laboratory of Experimental Medicine, A. Vésale Hospital, Faculty of Medicine, Université Libre de Bruxelles, Montigny-le-Tilleul, Belgium.
  • ,
  • Jean Nève, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Francois Dufrasne, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
  • ,
  • Pierre Van Antwerpen, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: pvantwer@ulb.ac.be.

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).

Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Volume123
Pages (from-to)746-62
Number of pages17
ISSN0223-5234
DOIs
Publication statusPublished - 10 Nov 2016

    Research areas

  • Journal Article

See relations at Aarhus University Citationformats

ID: 103700172