title: Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).
abstract: Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure-activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.
authors.affiliation: †Unité de Génomique Virale et Vaccination, Département de Virologie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|‡Unité Mixte de Recherche 3569, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Lucas-Hourani
authors.affiliation: §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.affiliation: ⊥Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, Texas 75390-9041, United States.
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.affiliation: #Unité de Biologie des Interactions Hôte-Parasite, Département de Parasitologie et Mycologie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.|^Unité 1201, Institut National de la Santé et de la Recherche Médicale, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|+Equipe de Recherche Labellisée 9195, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Malmquist
authors.affiliation: #Unité de Biologie des Interactions Hôte-Parasite, Département de Parasitologie et Mycologie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.|^Unité 1201, Institut National de la Santé et de la Recherche Médicale, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|+Equipe de Recherche Labellisée 9195, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Jane
authors.initials: J
authors.lastname: Harpon
authors.affiliation: §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Eloi P
authors.initials: EP
authors.lastname: Coutant
authors.affiliation: §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Guillou
authors.affiliation: §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Helynck
authors.affiliation: §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Noel
authors.affiliation: #Unité de Biologie des Interactions Hôte-Parasite, Département de Parasitologie et Mycologie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.|^Unité 1201, Institut National de la Santé et de la Recherche Médicale, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|+Equipe de Recherche Labellisée 9195, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
authors.affiliation: ⊥Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, Texas 75390-9041, United States.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: †Unité de Génomique Virale et Vaccination, Département de Virologie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|‡Unité Mixte de Recherche 3569, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tangy
authors.affiliation: †Unité de Génomique Virale et Vaccination, Département de Virologie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|‡Unité Mixte de Recherche 3569, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Vidalain
authors.affiliation: §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.|∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Yves L
authors.initials: YL
authors.lastname: Janin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008459:Measles virus / Q000187:drug effects / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D044925:Oxidoreductases Acting on CH-CH Group Donors