RESUMEN
Several 1,2,3,4-tetrahydro- and 7-N-hydroxycarbamate derivatives of the natural product rapamycin were prepared and assayed for their immunosuppressive and antifungal profiles. Substitutions at the 7-position indicate the possibility of a differentiated immunosuppressive to antifungal profile, whereas 40-position variants of the tetrahydro-analogues did not show similar differentiated activity.
Asunto(s)
Antifúngicos/farmacología , Sirolimus/análogos & derivados , Sirolimus/farmacología , Animales , Antifúngicos/química , Biofarmacia , Candida/efectos de los fármacos , Química Farmacéutica , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Transducción de Señal , Sirolimus/químicaRESUMEN
In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.
Asunto(s)
Antibacterianos/síntesis química , Eritromicina/análogos & derivados , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Diseño de Fármacos , Estabilidad de Medicamentos , Duodeno/efectos de los fármacos , Duodeno/fisiología , Eritromicina/síntesis química , Eritromicina/química , Eritromicina/metabolismo , Eritromicina/farmacología , Escherichia coli/efectos de los fármacos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Antro Pilórico/metabolismo , Conejos , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Neuropéptido/metabolismo , Staphylococcus aureus/efectos de los fármacos , Estereoisomerismo , Streptococcus/efectos de los fármacosRESUMEN
Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.