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

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(me...

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Published in:European journal of medicinal chemistry 2016-11, Vol.123, p.746-762
Main Authors: Aldib, Iyas, Gelbcke, Michel, Soubhye, Jalal, Prévost, Martine, Furtmüller, Paul G., Obinger, Christian, Elfving, Betina, Alard, Ibaa Chikh, Roos, Goedele, Delporte, Cédric, Berger, Gilles, Dufour, Damien, Zouaoui Boudjeltia, Karim, Nève, Jean, Dufrasne, Francois, Van Antwerpen, Pierre
Format: Article
Language:English
Subjects:
Amines - chemical synthesis
Amines - chemistry
Amines - metabolism
Amines - pharmacology
Bis-arylalkylamines derivatives
Chemical Sciences
Chemistry Techniques, Synthetic
Docking
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Halogenation
Humans
Kinetics
Medicinal Chemistry
Molecular Docking Simulation
Myeloperoxidase selective inhibitors
Oxidation-Reduction
Peroxidase - antagonists & inhibitors
Peroxidase - chemistry
Peroxidase - metabolism
Pharmacomodulation
Protein Conformation
Reversible inhibitors
Serotonin Uptake Inhibitors - chemical synthesis
Serotonin Uptake Inhibitors - chemistry
Serotonin Uptake Inhibitors - metabolism
Serotonin Uptake Inhibitors - pharmacology
SERT
Structure-Activity Relationship
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Summary: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). [Display omitted] •Bis-arylalkylamines were designed using docking experiments and synthesized.•They were tested against myeloperoxidase and their redox potentials were measured.•Eight compounds were more active than the starting hit.•They acted as reversible inhibitors of myeloperoxidase.•Docking experiments and chemical synthesis allow a comprehensive study of the SAR.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.07.053