Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors

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

  • Jalal Soubhye, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, 1050 Brussels, Belgium.
  • ,
  • Iyas Aldib
  • ,
  • Betina Elfving
  • Michel Gelbcke
  • ,
  • Paul G Furtmüller
  • ,
  • Manuel Podrecca
  • ,
  • Raphaël Conotte
  • ,
  • Jean-Marie Colet
  • ,
  • Alexandre Rousseau
  • ,
  • Florence Reye
  • ,
  • Ahmad Sarakbi
  • ,
  • Michel Vanhaeverbeek
  • ,
  • Jean-Michel Kauffmann
  • ,
  • Christian Obinger
  • ,
  • Jean Nève
  • ,
  • Martine Prévost
  • ,
  • Karim Zouaoui Boudjeltia
  • ,
  • Francois Dufrasne
  • ,
  • Pierre Van Antwerpen
Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume56
Issue10
Pages (from-to)3943-58
Number of pages16
ISSN0022-2623
DOIs
Publication statusPublished - 23 May 2013

    Research areas

  • Animals, Carboxylic Acids, Crystallization, Drug Design, Enzyme Inhibitors, Fluorine, Humans, Indicators and Reagents, Indoles, Lipoproteins, LDL, Male, Models, Molecular, Nitrogen, Oxidation-Reduction, Peroxidase, Rats, Rats, Wistar, Serotonin Uptake Inhibitors, Structure-Activity Relationship, Sulfur, Taurine

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