Design, Synthesis, and Efficacy Testing of Nitroethylene- and 7-Nitrobenzoxadiazol-Based Flavodoxin Inhibitors against Helicobacter pylori Drug-Resistant Clinical Strains and in Helicobacter pylori -Infected Mice

Sandra Salillas; Miriam Alías; Valérie Michel; Alejandro Mahía; Ainhoa Lucía; Liliana Rodrigues; Jessica Bueno; Juan José Galano-Frutos; Hilde de Reuse; Adrián Velázquez-Campoy; José Alberto Carrodeguas; Carlos Sostres; Javier Castillo; José Antonio Aínsa; María Dolores Díaz-De-Villegas; Angel Lanas; Eliette Touati; Javier Sancho

doi:10.1021/acs.jmedchem.9b00355

Journal articles

Design, Synthesis, and Efficacy Testing of Nitroethylene- and 7-Nitrobenzoxadiazol-Based Flavodoxin Inhibitors against Helicobacter pylori Drug-Resistant Clinical Strains and in Helicobacter pylori -Infected Mice

Design, synthèse et test d'efficacité des inhibiteurs de flavodoxine, Nitroethylene- et 7-Nitrobenzoxadiazole contre les souches clinniques antibio-resistantes d'Helicobacter pylori et dans les souris infectées

Sandra Salillas ^{1, 2, 3} Miriam Alías ^{1, 3} Valérie Michel ⁴ Alejandro Mahía ^{1, 2, 3} Ainhoa Lucía ^{2, 5, 6} Liliana Rodrigues ^{2, 6, 5} Jessica Bueno ⁶ Juan José Galano-Frutos ^{1, 3, 2} Hilde de Reuse ⁴ Adrián Velázquez-Campoy ^{1, 3, 2, 7} José Alberto Carrodeguas ^{1, 3, 2} Carlos Sostres ^{8, 2} Javier Castillo ⁶ José Antonio Aínsa ^{6, 1, 2, 5} María Dolores Díaz-De-Villegas ⁹ Angel Lanas ^{10, 2, 5} Eliette Touati ⁴ Javier Sancho ^{1, 2, 3}

1 BIFI - Instituto de Biocomputación y Física de Sistemas Complejos = Institute for Biocomputation and Physics of Complex Systems

2 Aragón Health Research Institute [Zaragoza, Spain]

3 Departamento de Bioquímica y Biología Molecular y Celular [Zaragoza]

4 Pathogenèse de Helicobacter - Helicobacter Pathogenesis

5 CIBERES - Centro de Investigación Biomédica en Red Enfermedades Respiratorias

6 Departamento de Microbiología, Medicina Preventiva y Salud Publica [Zaragoza]

7 Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain]

8 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas

9 Instituto de Síntesis Química y Catálisis Homogénea

10 Departamento de Medicina, Psiquiatría y Dermatologíae [Zaragoza, Spain]

Abstract : Helicobacter pylori (Hp) infection is the main cause of peptic ulcer and gastric cancer. Hp eradication rates have fallen due to increasing bacterial resistance to currently used broad-spectrum antimicrobials. We have designed, synthesized, and tested redox variants of nitroethylene- and 7-nitrobenzoxadiazole-based inhibitors of the essential Hp protein flavodoxin. Derivatives of the 7-nitrobenzoxadiazole lead, carrying reduced forms of the nitro group and/or oxidized forms of a sulfur atom, display high therapeutic indexes against several reference Hp strains. These inhibitors are effective against metronidazole-, clarithromycin-, and rifampicin-resistant Hp clinical isolates. Their toxicity for mice after oral administration is low, and, when administered individually at single daily doses for 8 days in a mice model of Hp infection, they decrease significantly Hp gastric colonization rates and are able to eradicate the infection in up to 60% of the mice. These flavodoxin inhibitors constitute a novel family of Hp-specific antimicrobials that may help fight the constant increase of Hp antimicrobial-resistant strains.

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Journal articles

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Life Sciences [q-bio] / Human health and pathology / Infectious diseases

Chemical Sciences / Medicinal Chemistry

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