Improved flavodoxin inhibitors with potential therapeutic effects against Helicobacter pylori infection

Galano, J. J. (Universidad de Zaragoza) ; Alías, M. ; Pérez, R. ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; Hoffman, P. S. ; Sancho, J. (Universidad de Zaragoza)

Resumen: Helicobacter pylori (Hp) infection affects onehalf of the human population and produces a variety of diseases from peptic ulcer to cancer. Current eradication therapies achieve modest success rates (around 70%), resistance to the antibiotics of choice is on the rise, and vaccination has not proved to be successful yet. Using an essential Hp protein, flavodoxin, as target, we identified three low-molecular-weight flavodoxin inhibitors with bactericidal anti-Hp properties. To improve their therapeutic indexes, we have now identified and tested 123 related compounds. We have first tested similar compounds available. Then we have designed, synthesized, and tested novel variants for affinity to flavodoxin, MIC for Hp, cytotoxicity, and bactericidal effect. Some are novel bactericidal inhibitors with therapeutic indexes of 9, 38 and 12, significantly higher than those of their corresponding leads. Developing novel Hp-specific antibiotics will help fighting Hp resistance and may have the advantage of not generally perturbing the bacterial flora.

Idioma: Inglés

DOI: 10.1021/jm400786q

Año: 2013

Publicado en: Journal of medicinal chemistry 56, 15 (2013), 6248-6258
ISSN: 0022-2623

Factor impacto JCR: 5.48 (2013)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 3 / 58 = 0.052 (2013) - Q1 - T1

Tipo y forma: Artículo (PostPrint)

Área (Departamento): Proy. investigación DEA (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)