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
The design and synthesis of novel 15-membered 11-azalides and 16-membered 11,12-diazalide starting from 16-membered macrolides are reported. A mobile linear dialdehyde was isolated via a cyclic tetraol which was prepared by osmium oxidation of a conjugated diene. One-pot macrocyclization of this dialdehyde with an amine or a diamine afforded corresponding 15-membered azalides or 11,12-diazalide. Fundamental SAR studies of 15-membered 11-azalides disclosed their potentiality as a lead molecule for further chemical modifications. For environmental preservation, sustainable chemistry for synthesis of these azalides is also discussed.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Compuestos Aza/síntesis química , Azitromicina/análogos & derivados , Macrólidos/síntesis química , Macrólidos/farmacología , Antibacterianos/química , Compuestos Aza/farmacología , Azitromicina/química , Azitromicina/farmacología , Bacterias/efectos de los fármacos , Humanos , Kitasamicina/síntesis química , Kitasamicina/farmacología , Compuestos Macrocíclicos , Macrólidos/química , Pruebas de Sensibilidad Microbiana , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/síntesis química , Uridina Monofosfato/farmacologíaRESUMEN
A small library of leucomycin A7 derivatives was prepared by NaCNBH3/ZnCl2-mediated reductive amination of the C18 aldehyde moiety with a variety of lipophilic benzylamines and tested for antibiotic activity.
Asunto(s)
Antibacterianos/síntesis química , Kitasamicina/análogos & derivados , Kitasamicina/síntesis química , Aldehídos , Aminas , Antibacterianos/farmacología , Indicadores y Reactivos , Kitasamicina/farmacología , Pruebas de Sensibilidad Microbiana , Oxidación-ReducciónRESUMEN
An efficient procedure for the highly selective oxidation of leucomycines to the corresponding 16-membered 9- and 13-oxo macrolides using hypervalent iodinates is presented. Both the Dess-Martin periodinane (DMP) and polymer-bound 2-iodoxybenzoic acid (IBX) show clear advantages over the previously employed manganese dioxide. Key intermediates for a variety of further chemical derivatization methods (2a, 2b) are obtained in very good yields without the requirement of protecting groups.