RESUMEN
A series of 10,13-disubstituted 16-membered macrolides was synthesized using nitroso Diels-Alder reactions of leucomycin A7. Despite the extensive constituent functionalities in leucomycin, the hetero cycloaddition reactions proceeded in a highly regio- and stereoselective fashion. Subsequent chemical modifications of the nitroso cycloadducts, including N-O bond reduction, were also conducted. Most leucomycin derivatives retained antibiotic profiles similar to leucomycin A7, and, in contrast to leucomycin itself, several exhibited moderate antiproliferative and cytotoxic activity.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Kitasamicina/análogos & derivados , Kitasamicina/farmacología , Compuestos Nitrosos/química , Animales , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Bacterias/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Kitasamicina/síntesis química , Kitasamicina/química , Kitasamicina/toxicidad , Ratones , Relación Estructura-ActividadRESUMEN
The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macrolides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously reported. Sequential macrocyclization of the formylcarboxylic acid with amino alcohol followed by deprotection afforded corresponding 14- to 16-membered azalides. On the other hand, reductive amination of the formylcarboxylic acid with an azidoamine followed by macrolactam formation with an amine generated from the azide gave 14- to 16-membered azalactams. Among these derivatives, 15-membered azalactams and 16-membered azalides exhibited characteristic in vitro antibacterial activities. Although optimization of 15-membered azalactams including demycarosyl analogues did not provide remarkably promising molecules, SAR studies of 16-membered azalides disclosed that substitution at the 15 position was very important for identification of a clinical candidate.
Asunto(s)
Antibacterianos/síntesis química , Compuestos Aza/síntesis química , Macrólidos/síntesis química , Amino Alcoholes/química , Antibacterianos/química , Antibacterianos/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Azitromicina/análogos & derivados , Azitromicina/farmacología , Ácidos Carboxílicos/química , Kitasamicina/síntesis química , Kitasamicina/química , Kitasamicina/farmacología , Macrólidos/química , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully protected intermediate (5), appropriate modifications including Heck reaction were performed to furnish 3-O-(3-aryl-2-propenyl)leucomycin A(7) analogues (9a-9m). These leucomycin A(7) derivatives showed improved in vitro antibacterial activities against clinically important pathogens including erythromycin-resistant Streptococcus pneumoniae (ERSP). SAR analysis of derivatives modified at the C-3 and C-3'' positions suggested that single modification at C-3 or C-3'' was effective for in vitro antibacterial activity.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Diseño de Fármacos , Kitasamicina/síntesis química , Kitasamicina/farmacología , Antibacterianos/química , Benzoquinonas/química , Cristalografía por Rayos X , Kitasamicina/análogos & derivados , Kitasamicina/química , Miocamicina/análogos & derivados , Miocamicina/síntesis química , Miocamicina/química , Miocamicina/farmacología , Modelos Moleculares , Estructura Molecular , Streptococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
AIM: To identify the components of acetylleucomycin and its hydrolytic products by LC-MS. METHODS: Acetylleucomycin was separated on a Diamonsil C18 column with 0.1 mol x L(-1) ammonium acetate-acetontrile (35 : 65) as mobile phase. The LC-MS was equipped with an electorspray ion source (ESI), which was set at the positive ion mode, and the mass spectra of each component in chromatogram were obtained with difference cone voltage. RESULTS: The components of acetylleucomycin and its hydrolytic products can be separated by HPLC. The components were identified according to the molecular weight and its major mass fragment ions. The major components identified in domastic acetylleucomycin were acetylleucomycin A4, A5; acetylleucomycin A1, A3; acetylleucomycin A6, A7, and acetylleucomycin A13. The hydrolytic products of acetylleucomycin were not kitasamycin, but some non-complete hydrolytic product. CONCLUSION: The method is rapid, sensitive and specific. It' s suitable to application in the fields of multi-components antibiotics analysis.
Asunto(s)
Kitasamicina/análogos & derivados , Kitasamicina/análisis , Espectrometría de Masa por Ionización de Electrospray/métodos , Cromatografía Liquida/métodos , Hidrólisis , Josamicina/análisis , Josamicina/química , Kitasamicina/química , Leucomicinas/análisis , Leucomicinas/química , Macrólidos/análisis , Macrólidos/químicaRESUMEN
The investigation of a dichloromethane extract of flower heads of a Hungarian taxon of the Achillea millefolium group led to the isolation of three flavonoid aglycones, one triterpene, one germacranolide and five guaianolides. Their structures were elucidated by UV-VIS, EI- and CI-MS, 1H NMR and 13C NMR spectroscopic methods as well as by 2D-NMR studies and by selective 1D-NOE experiments. Besides apigenin, luteolin and centaureidin, beta-sitosterol, 3beta-hydroxy-11alpha,13-dihydro-costunolide, desacetylmatricarin, leucodin, achillin, 8alpha-angeloxy-leucodin and 8alpha-angeloxy-achillin were isolated. Both latter substances are reported here for the first time. Their NMR data were compared with those of the other guaianolides. The stereochemistry of 3beta-hydroxy-11alpha,13-dihydro-costunolide was discussed and compared with data of the literature.
Asunto(s)
Achillea/química , Flavonoides/química , Sesquiterpenos/química , Flavonoides/aislamiento & purificación , Kitasamicina/química , Kitasamicina/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Sesquiterpenos/aislamiento & purificación , Espectrofotometría InfrarrojaRESUMEN
Swine dysentery and poultry cholera are very harmful animal diseases which cause great damage. Flumequine and kitasamycin are new and up-to-date preparations for the treatment of these diseases. ++ Imequyl ad us. vet. and ++ Trubin ad us. vet. are the registered medicines. The doses are 7 mg flumequine and 21 mg kitasamycin/body weight kg. The drug technological problem is that flumequine does not dissolve sufficiently in water. It dissolves well at pH = 10, but kitasamycin is unstable at this pH. It was hoped that these two components would together act as agonists, and that kitasamycin would promote the dissolution of flumequine. An injection preparation and a powder mixture for dissolution were developed. Chemical interaction between the components was conformed by IR and NMR measurements.