Design, Synthesis, and Structure-Activity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors
[en] 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.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Soubhye, Jalal
Aldib, Iyas
Elfving, Betina
Gelbcke, Michel
Furtmuller, Paul G.
Podrecca, Manuel ; Université de Mons > Faculté de Médecine et de Pharmacie > Biologie humaine et Toxicologie
Conotte, Raphael ; Université de Mons > Faculté de Médecine et de Pharmacie > Biologie humaine et Toxicologie
Colet, Jean-Marie ; Université de Mons > Faculté de Médecine et de Pharmacie > Biologie humaine et Toxicologie
Rousseau, Alexandre
Reyé, Florence
Sarakbi, A.
Vanhaeverbeek, Michel ; Université de Mons > Faculté de Médecine et de Pharmacie > FMP - Service du Doyen
Kauffmann, Jean-Michel
Obinger, Christian
Nève, Jean
Prevost, Martine
Zouaoui Boudjeltia, Karim ; Université de Mons > Faculté de Médecine et de Pharmacie > FMP - Service du Doyen
Dufrasne, François ; Université de Mons > Faculté de Médecine et de Pharmacie > Service de Chimie thérapeutique et Pharmacognosie
Design, Synthesis, and Structure-Activity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors
Publication date :
23 May 2013
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
Publisher :
American Chemical Society, United States - District of Columbia
Volume :
56
Issue :
10
Pages :
3943-3958
Peer reviewed :
Peer Reviewed verified by ORBi
Research unit :
M125 - Biologie humaine et Toxicologie M136 - Chimie thérapeutique et Pharmacognosie
Research institute :
R550 - Institut des Sciences et Technologies de la Santé
Harrison, J. E.; Schultz, J. J. Biol. Chem. 1976, 251, 1371-1374
Klebanoff, S. J. Myeloperoxidase: Friend and foe J. Leukocyte Biol. 2005, 77, 598-562
Schultz, J.; Kaminker, K. Arch. Biochem. Biophys. 1962, 96, 465-467
Salmon, S. E.; Cline, M. J.; Schultz, J.; Lehrer, R. I. N. Engl. J. Med. 1970, 282, 250-253
Segal, A. W. Annu. Rev. Immunol. 2005, 23, 197-223
Fiedler, T. J.; Davey, C.; Fenna, R. X-ray crystal structure and characterization of halide-binding sites of human myeloperoxidase at 1.8 A resolution J. Biol. Chem. 2000, 275 (16) 11964-11971
Arnhold, J.; Flemmig, J. Human myeloperoxidase in innate and acquired immunity Arch. Biochem. Biophys. 2010, 500 (1) 92-106
Baldus, S.; Heeschen, C.; Meinertz, T.; Zeiher, A. M.; Eiserich, T.; Münzel, J. P.; Simoons, M. L.; Hamm, C. W. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes Circulation 2003, 108, 1440-1445
Libby, P.; Radker, P.; Hansson, G. Progress and challenges in translating the biology of atherosclerosis Nature 2011, 473, 317-325
Barter, P. The inflammation: lipoprotein cycle Atheroscler. Suppl. 2005, 6, 15-20
Chisolm, G.; Steinberg, D. The oxidative modification hypothesis of atherogenesis: an overview Free Radical Biol. Med. 2000, 28, 1815-1826
Van Antwerpen, P.; Boudjeltia, K.; Babar, S.; Legssyer, I.; Moreau, P.; Moguilevsky, N.; Vanhaeverbeek, M.; Ducobu, J.; Nève, J. Thiol-containing molecules interact with the myeloperoxidase/H2O2/chloride system to inhibit LDL oxidation Biochem. Biophys. Res. Commun. 2005, 337, 82-88
Carr, A. C.; Decker, E. A.; Park, Y.; Frei, B. Comparison of low-density lipoprotein modification by myeloperoxidase-derived hypochlorous and hypobromous acids Free Radical Biol. Med. 2001, 31, 62-72
Nicholls, S. J.; Hazen, S. L. Myeloperoxidase and cardiovascular disease Arterioscler. Thromb. Vasc. Biol. 2005, 25 (6) 1102-1111
Nève, J.; Parij, N.; Moguilevsky, N. Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs investigated with human recombinant enzyme Eur. J. Pharmacol. 2001, 417, 37-43
Van Antwerpen, P.; Dufrasne, F.; Lequeux, M.; Zouaoui-Boudjeltia, K.; Lessgyer, I.; Babar, S.; Moreau, P.; Moguilevsky, N.; Vanhaeverbeek, M.; Ducobu, J.; Neve, J. Inhibition of the myeloperoxidase chlorinating activity by nonsteroidal anti-inflammatory drug flufenamic acid and its 5-chloro-derivative directly interact with a recombinant human myeloperoxidase to inhibit the synthesis of hypochlorous acid Eur. J. Pharmacol. 2007, 570, 235-243
Van Antwerpen, P.; Prévost, M.; Zouaoui-Boudjeltia, K.; Babar, S.; Legssyer, I.; Moreau, P.; Moguilevsky, N.; Vanhaeverbeek, M.; Ducobu, J.; Neve, J.; Dufrasne, F. Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification Med. Chem. 2008, 16, 1702-1720
Kettle, A.; Gedye, C.; Hampton, M. B.; Winterbourn, C. C. Inhibition of myeloperoxidase by benzoic acid hydrazides Biochem. J. 1995, 308 (Pt 2) 559-563
Ikeda-Saito, M.; Shelley, D.; Lu, L.; Booth, K.; Caughey, W.; Kimura, S. Salicylhydroxamic acid inhibits myeloperoxidase activity J. Biol. Chem. 1991, 266 (6) 3611-6
Hanson, S.; Nordvall, G.; Tiden, A. K. Preparation of xanthinethione derivatives as myeloperoxidase inhibitors. PCT Int. Appl. WO 2003089430 A1 20031030, 2003.
Regasini, L. O.; Vellosa, J. C. R.; Silva, D. H. S.; Furlan, M.; de Oliveira, O.M. M.; Khalil, N. M.; Brunetti, I. L.; Young, M. C. M.; Barreiro, E. J.; Bolzani, V. S. Flavonols from Pterogyne nitens and their evaluation as myeloperoxidase inhibitors Phytochemistry 2008, 69 (8) 1739-1744
Shiba, Y.; Kinoshita, T.; Chuman, H.; Taketani, Y.; Takeda, E.; Kato, Y.; Naito, M.; Kawabata, K.; Ishisaka, A.; Terao, J.; Kawai, Y. Flavonoids as substrates and inhibitors of myeloperoxidase: molecular actions of aglycone and metabolites Chem. Res. Toxicol. 2008, 21 (8) 1600-1609
Galijasevic, S.; Abdulhamid, I.; Abu-Soud, H. M. Melatonin is a potent inhibitor for myeloperoxidase Biochemistry 2008, 47 (8) 2668-2677
Ximenes, V. F.; Paino, I. M. M.; Faria-de Oliveira, O. M. M.; Fonseca, L. M. D.; Brunetti, I. L. Indole ring oxidation by activated leukocytes prevents the production of hypochlorous acid Braz. J. Med. Biol. Res. 2005, 38 (11) 1575-1583
Van Antwerpen, P.; Moreau, P.; Zouaoui-Boudjeltia, K.; Babar, S.; Dufrasne, F.; Moguilevsky, N.; Vanhaeverbeek, M.; Ducobu, J.; Neve, J. Development and validation of screening procedure for the assessment of inhibition using a recombinant enzyme Talanta 2008, 75, 503-510
Soubhye, J.; Prévost, M.; Van Antwerpen, P.; Boudjeltia, K.; Rousseau, A.; Furtmuller, P.; Obinger, C.; Vanhaeverbeek, M.; Ducobu, J.; Neve, J.; Gelbcke, M.; Dufrasne, F. Structure-based design, synthesis, and pharmacological evaluation of 3-(aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors J. Med. Chem. 2010, 53 (24) 8747-8759
Rupp, A.; Kovar, K.-A.; Beuerle, G.; Ruf, C.; Folkers, G. A new pharmacophoric model for 5-HT reuptake-inhibitors: differentiation of amphetamine analogs Pharm. Acta Helv. 1994, 68, 235-244
Campos, K.; Woo, J.; Lee, S.; Tillyer, R. A general synthesis of substituted indoles from cyclic enol ethers and enol lactones Org. Lett. 2004, 6, 79-82
Deo, M. Di.; Marcantoni, E.; Torregiani, E.; Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, v. Simple, efficient, and general method for the conversion of alcohols into alkyl iodides by a CeCl3·7H 2O/NaI system in acetonitrile J. Org. Chem. 2000, 65, 2830-2833
Dufrasne, F.; Nève, J. Synthesis of 1,2-diamino-1-phenylpropane diastereoisomers from u-N-trifluoroacetyl-2-amino-1-phenylpropan-1-ol Monatsh. Chem. 2005, 163, 739-746
Mewshaw, R. E.; Zhou, D.; Zhou, P.; Shi, X.; Hornby, G.; Spangler, T.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree, T. H. Studies toward the discovery of the next generation of antidepressants. 3. Dual 5-HT1A and serotonin transporter affinity within a class of N- aryloxyethylindoleylalkylamines J. Med. Chem. 2004, 47, 3823-3842
Stevenson, R.; Sant Milid, P.; Haider, R.; Hilmi, A.; Al Farham, E. Method for making substituted indole. PCT Int. Appl. WO9959970, 1999.
Hatzenbuhler, N. T.; Evrard, D. A.; Mewshaw, R. E.; Zhou, D.; Shah, U. S.; Inghrim, J. A.; Lenicek, S. E.; Baudy, R. B.; Butera, J. A.; Sabb, A. L.; Failli, A. A.; Ramamoorthy, P. S. A preparation of 3-aminochroman and 2-aminotetralin derivatives, useful in the treatment of serotonin-mediated disorders. PCT Int. Appl. WO2005012291, 2005.
Hall, H.; Gisler, M. A Simple method for converting nitriles to amides. Hydrolysis with potassium hydroxide in tert-butyl alcohol J. Org. Chem. 1976, 41, 3769-3770
Jantschko, W.; Furtmuller, G. P.; Zederbauer, M.; Neugschwandtner, K.; Lehner, I.; Jakopitsch, C.; Arnhold, J.; Obinger, C. Exploitation of the unusual thermodynamic properties of human myeloperoxidase in inhibitor design Biochem. Pharmacol. 2005, 69, 1149-1157
Schmitz, W.; William, D.; Brenner, J.; Ditta, A.; Mattson, R.; Mattson, G.; Molski, T.; Macor, J. Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs) Bioorg. Med. Chem. Lett. 2005, 15, 1619-1621
Franck, T.; Kohnen, S.; Boudjeltia, K. Z.; Van Antwerpen, P.; Bosseloir, A.; Niesten, A.; Gach, O.; Nys, M.; Deby-Dupont, G.; Serteyn, D. A new easy method for specific measurement of active myeloperoxidase in human biological fluids and tissue extracts Talanta 2009, 80, 723-729
Blair-Johnson, M.; Fiedler, T.; Fenna, R. Human myeloperoxidase: structure of a cyanide complex and its interaction with bromide and thiocyanate substrates at 1.9 Å resolution Biochemistry 2001, 40, 13990-1399
Sadowski, J.; Gasteiger, J. From atoms and bonds to three-dimensional atomic coordinates: automatic model builders Chem. Rev. 1993, 93, 2567-2581
Aldib, I.; Soubhye, J.; Zouaoui Boudjeltia, K.; Vanhaeverbeek, M.; Rousseau, A.; Furtmüller, P.; Obinger, C.; Dufrasne, F.; Nève, J.; Van Antwerpen, P.; Prévost, M. Evaluation of new scaffolds of myeloperoxidase inhibitors by rational design combined with high-throughput virtual screening J. Med. Chem. 2012, 55 (16) 7208-7218
Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy J. Med. Chem. 2004, 47, 1739-1794
Shelley, J. C.; Cholleti, A.; Frye, L. L.; Greenwood, J. R.; Timlin, M. R.; Uchimaya, M. Epik: a software program for pK(a) prediction and protonation state generation for drug-like molecules J. Comput.-Aided Mol. Des. 2007, 21, 681-691
Havel, R. J.; Eder, H. A.; Bragdon, J. H. Distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum J. Clin. Invest. 1955, 34, 1345-1353
Hewson, W. D.; Hager, L. P. Mechanism of the chlorination reaction catalyzed by horseradish peroxidase with chlorite J. Biol. Chem. 1979, 254, 3175-3181
Moguilevsky, N.; Zouaoui-Boudjeltia, Z.; Babar, S.; Delre'e, P.; Legssyer, I.; Carpentier, Y.; Vanhaeverbeek, M.; Ducobu, J. Monoclonal antibodies against LDL progressively oxidized by myeloperoxidase react with ApoB-100 protein moiety and human atherosclerotic lesions Biochem. Biophys. Res. Commun. 2004, 323, 1223-1228
Furtmuller, P. G.; Burner, U.; Obinger, C. Reaction of human myeloperoxidase compound I with chloride, bromide, iodide, and thiocyanate Biochemistry 1998, 37, 17923-17930
Kristensen, A.; Larsen, M.; Johnsen, L.; Wiborg, O. Mutational scanning of the human serotonin transporter reveals fast translocating serotonin transporter mutants Eur. J. Neurosci. 2004, 19, 1513-1523
Larsen, M.; Elfving, B.; Wiborg, O. The chicken serotonin transporter discriminates between serotonin-selective reuptake inhibitors: A species-scanning mutagenesis study J. Biol. Chem. 2004, 279, 42147-42156
Estevão, M. S.; Carvalho, L. C.; Ferreira, L. M.; Fernandes, E.; Marques, M. M. B. Analysis of the antioxidant activity of an indole library: cyclic voltammetry Tetrahedron Lett. 2010, 52, 101-106
Garrels, R.; Christ, C. Minerals, Solutions, and Equilibria; Jones and Bartlett: Sudbury, MA, 1990.
