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

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

Resumen: 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.

Idioma: Inglés

DOI: 10.1021/acs.jmedchem.9b00355

Año: 2019

Publicado en: Journal of medicinal chemistry 62, 13 (2019), 6102-6115
ISSN: 0022-2623

Factor impacto JCR: 6.205 (2019)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 3 / 61 = 0.049 (2019) - Q1 - T1

Factor impacto SCIMAGO: 2.093 - Molecular Medicine (Q1) - Drug Discovery (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-17R
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI11-02578
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Microbiología (Dpto. Microb.Med.Pr.,Sal.Públ.)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)