doi:10.1021/acs.jmedchem.9b00355engSalillas, SandraAlías, MiriamMichel, ValérieMahía, AlejandroLucía, AinhoaRodrigues, LilianaBueno, JessicaGalano-Frutos, Juan JoséDe Reuse, HildeVelázquez-Campoy, AdriánCarrodeguas, José AlbertoSostres, CarlosCastillo, JavierAínsa. José AntonioDíaz-de-Villegas, María DoloresLanas, ÁngelTouati, ElietteSancho, JavierDesign, synthesis, and efficacy testing of nitroethylene- and 7-nitrobenzoxadiazol-based flavodoxin inhibitors against helicobacter pylori drug-resistant clinical strains and in helicobacter pylori-infected miceART-2019-112597Helicobacter 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.2019http://zaguan.unizar.es/record/13041910.1021/acs.jmedchem.9b00355http://zaguan.unizar.es/record/130419oai:zaguan.unizar.es:130419info:eu-repo/grantAgreement/ES/DGA/E45-17Rinfo:eu-repo/grantAgreement/ES/FIS/PI11-02578info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-PJournal of medicinal chemistry 62, 13 (2019), 6102-6115All rights reservedhttp://www.europeana.eu/rights/rr-f/info:eu-repo/semantics/openAccess