RESUMEN
Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.
Asunto(s)
Antibacterianos/síntesis química , Azitromicina/síntesis química , Macrólidos/síntesis química , Microsomas Hepáticos/efectos de los fármacos , Infecciones Neumocócicas/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Administración Oral , Animales , Antibacterianos/farmacocinética , Azitromicina/análogos & derivados , Azitromicina/farmacocinética , Disponibilidad Biológica , Ácidos Carboxílicos/química , Cristalografía por Rayos X , Estabilidad de Medicamentos , Ésteres/química , Humanos , Inyecciones Intravenosas , Macrólidos/farmacocinética , Masculino , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Infecciones Neumocócicas/microbiología , Ratas , Ratas Wistar , Streptococcus pneumoniae/crecimiento & desarrolloRESUMEN
The synthesis and antimicrobial activity of a new class of macrolide antibiotics which consist of a macrolide scaffold and a quinolone unit covalently connected by an appropriate linker are described. Optimization of several synthetic steps and structural properties of lead compound 26 are discussed. Promising antibacterial properties of this compound and some of its analogues are reported.
Asunto(s)
Antibacterianos/síntesis química , Macrólidos/síntesis química , Macrólidos/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Microbiana , Humanos , Macrólidos/química , Conformación Molecular , Estructura Molecular , Quinolonas/química , Relación Estructura-ActividadRESUMEN
Ethyl 1-ethyl-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate, C14H14INO3, (I), and ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate, C15H14INO3, (II), have isomorphous crystal structures, while ethyl 1-dimethylamino-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate, C14H15IN2O3, (III), possesses a different solid-state supramolecular architecture. In all three structures, O...I halogen-bonding interactions connect the quinolone molecules into infinite chains parallel to the unique crystallographic b axis. In (I) and (II), these molecular chains are arranged in (101) layers, via pi-pi stacking and C-H...pi interactions, and these layers are then interlinked by C-H...O interactions. The structural fragments involved in the C-H...O interactions differ between (I) and (II), accounting for the observed difference in planarity of the quinolone moieties in the two isomorphous structures. In (III), C-H...O and C-H...pi interactions form (100) molecular layers, which are crosslinked by O...I and C-H...I interactions.