RESUMEN
A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.
Asunto(s)
Antibacterianos/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , ADN Bacteriano/química , ADN Bacteriano/efectos de los fármacos , ADN Superhelicoidal/efectos de los fármacos , Haemophilus influenzae/efectos de los fármacos , Alcoholes/química , Antibacterianos/síntesis química , Antibacterianos/química , Benzotiazoles/síntesis química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Staphylococcus , Relación Estructura-ActividadRESUMEN
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , Diseño de Fármacos , Ácidos Isonipecóticos/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Benzotiazoles/síntesis química , Girasa de ADN/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/enzimología , Activación Enzimática/efectos de los fármacos , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/enzimología , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/enzimología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacocinéticaRESUMEN
Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.
Asunto(s)
Acetilcolinesterasa/metabolismo , Carbazoles/química , Carbazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Acetilcolinesterasa/química , Acetilcolinesterasa/farmacocinética , Acetilcolinesterasa/uso terapéutico , Animales , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Compuestos Aza/uso terapéutico , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Cristalografía por Rayos X , Perros , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/química , RatasRESUMEN
The total syntheses of the 3,6-dihydroxydecanolide from Cordyceps militaris and the novel C-3 epimer are reported using a diastereoselective Nozaki-Hiyama-Kishi reaction in the key cyclization to generate the 6R stereocenter.
Asunto(s)
Productos Biológicos/síntesis química , Cordyceps/química , Lactonas/síntesis química , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Ciclización , Lactonas/química , Lactonas/aislamiento & purificación , Estructura Molecular , EstereoisomerismoAsunto(s)
Lactonas/aislamiento & purificación , Complejos Multienzimáticos/química , Reacción en Cadena de la Polimerasa/métodos , Antifúngicos/química , Ascomicetos/enzimología , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/aislamiento & purificación , Proteínas Fúngicas/metabolismo , Espectroscopía de Resonancia Magnética , Modelos Químicos , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/aislamiento & purificación , Complejos Multienzimáticos/metabolismoRESUMEN
A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.