title: Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study.
abstract: 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).
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Iyas
authors.initials: I
authors.lastname: Aldib
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Gelbcke
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jalal
authors.initials: J
authors.lastname: Soubhye
authors.affiliation: Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Prévost
authors.affiliation: 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.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Furtmüller
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Obinger
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
authors.affiliation: Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Ibaa Chikh
authors.initials: IC
authors.lastname: Alard
authors.affiliation: Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Goedele
authors.initials: G
authors.lastname: Roos
authors.affiliation: 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.
authors.forename: Cédric
authors.initials: C
authors.lastname: Delporte
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: Damien
authors.initials: D
authors.lastname: Dufour
authors.affiliation: Laboratory of Experimental Medicine, A. Vésale Hospital, Faculty of Medicine, Université Libre de Bruxelles, Montigny-le-Tilleul, Belgium.
authors.forename: Karim
authors.initials: K
authors.lastname: Zouaoui Boudjeltia
authors.affiliation: 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.
authors.forename: Jean
authors.initials: J
authors.lastname: Nève
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Francois
authors.initials: F
authors.lastname: Dufrasne
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D009195:Peroxidase; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Bis-arylalkylamines derivatives; Docking; Myeloperoxidase selective inhibitors; Pharmacomodulation; Reversible inhibitors; SERT