RESUMEN
A series consisting of new polyaminoisoprenyl derivatives were prepared in moderate to good chemical yields varying from 32 to 64% according to two synthetic pathways: (1) using a titanium-reductive amination reaction affording a 50/50 mixture of cis and trans isomers and (2) a direct nucleophilic substitution leading to a stereoselective synthesis of the compounds of interest. These compounds were then successfully evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria of four antibiotics belonging to four different families. The mechanism of action against Enterobacter aerogenes of one of the most efficient of these chemosensitizing agents was precisely evaluated by using fluorescent dyes to measure outer-membrane permeability and to determine membrane depolarization. The weak cytotoxicity encountered led us to perform an in vivo experiment dealing with the treatment of mice infected with Salmonella typhimurium and affording preliminary promising results in terms of tolerance and efficiency of the polyaminoisoprenyl derivative 5r/doxycycline combination.
Asunto(s)
Antibacterianos/uso terapéutico , Enterobacter/efectos de los fármacos , Poliaminas/uso terapéutico , Salmonelosis Animal/tratamiento farmacológico , Salmonella/efectos de los fármacos , Terpenos/uso terapéutico , Animales , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Poliaminas/síntesis química , Poliaminas/toxicidad , Terpenos/síntesis química , Terpenos/toxicidadRESUMEN
We report the synthesis and the characterization of a trinuclear nickel complex. Solid state and solution studies using X-ray diffraction, NMR and UV-vis spectroscopy highlight the square planar geometries around the metal centers and an all-sulfur coordination sphere. It exhibits significant electrocatalytic activity for hydrogen evolution in DMF using Et3NHCl as the proton source. DFT studies suggest that sulfur atoms act as proton relay, as proposed in [NiFe] hydrogenases.
RESUMEN
A series consisting of ianthelliformisamimes A, B, and C as well as its synthetic analogues was prepared in high chemical yield, from 27 to 91%, using peptide coupling as the key step, and the compounds were evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria and clinical isolates. The mechanism of action of one of these derivatives against Pseudomonas aeruginosa when combined with doxycycline was precisely evaluated utilizing bioluminescence to measure ATP efflux and fluorescence to evaluate membrane depolarization.