RESUMEN

Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.

Asunto(s)

ADN-Topoisomerasas de Tipo II/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Animales , Química Física , Perros , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/metabolismo , Ratas , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química

RESUMEN

A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.

Asunto(s)

Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Piperidinas/síntesis química , Piperidinas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/química , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Ratas , Relación Estructura-Actividad , Tiazoles/química , Ensayos Antitumor por Modelo de Xenoinjerto