RESUMEN
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.
Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinonas/farmacología , Tiazinas/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/químicaRESUMEN
Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.
Asunto(s)
Amidas/química , Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/química , VIH-1/enzimología , Amidas/síntesis química , Amidas/farmacocinética , Animales , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , Semivida , Compuestos Heterocíclicos/química , Humanos , Masculino , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICsAsunto(s)
Antibacterianos/síntesis química
, Antibacterianos/química
, Antibacterianos/farmacología
, Diterpenos/síntesis química
, Diterpenos/química
, Diterpenos/farmacología
, Pruebas de Sensibilidad Microbiana
, Compuestos Policíclicos
, Staphylococcus aureus/efectos de los fármacos
, Streptococcus pneumoniae/efectos de los fármacos
, Relación Estructura-Actividad
, Pleuromutilinas
RESUMEN
Stereoselective reduction of dehydroalanine double bond in nocathiacin I afforded the primary amide 2. Enzymatic hydrolysis of the amide 2 provided the carboxylic acid 3, which upon coupling with a variety of amines furnished amides 4-32. Some of these semi-synthetic derivatives have retained very good antibacterial activity and have improved aqueous solubility.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Enterococcus faecalis/efectos de los fármacos , Péptidos/síntesis química , Péptidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/química , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos/química , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Agua/químicaRESUMEN
The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity.
Asunto(s)
Antibacterianos/síntesis química , Péptidos/síntesis química , Compuestos de Sulfhidrilo/síntesis química , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Femenino , Péptidos y Proteínas de Señalización Intercelular , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Péptidos/administración & dosificación , Péptidos/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
[reaction: see text] Alkyl/aryl amidoximes, prepared from the corresponding nitriles and N-alkylhydroxylamines, have readily undergone consecutive Michael additions to electron-deficient alkynes and provided highly substituted 1,2,4-oxadiazolines in good yields in homogeneous aqueous solution.
Asunto(s)
Técnicas Químicas Combinatorias , Nitrilos/química , Oxadiazoles/síntesis química , Alquinos/síntesis química , Estructura Molecular , Oximas/síntesis química , Soluciones , Agua/químicaRESUMEN
Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.
Asunto(s)
Antibacterianos , Péptidos , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/crecimiento & desarrollo , Péptidos y Proteínas de Señalización Intercelular , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos/síntesis química , Péptidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
The synthesis and antibacterial activity of a series of new nocathiacin I derivatives (1-12) containing polar water solubilizing groups is described. Most of these compounds exhibited potent antibacterial activity and have improved water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo activity.
Asunto(s)
Antibacterianos/síntesis química , Péptidos/síntesis química , Antibacterianos/farmacología , Enterococcus faecalis/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular , Pruebas de Sensibilidad Microbiana , Péptidos/farmacología , Solubilidad , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-Actividad , Agua/químicaRESUMEN
Several semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity. Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation. Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile. A one-pot protection-alkylation-deprotection strategy was developed for the preparation of mono-O-alkyl hydroxypyridine analogues 5a,b. Most of the bis- and mono-O-alkyl nocathiacins maintained good in vitro activity but showed reduced in vivo efficacy when compared with the natural product. The excellent in vivo activity and improved water solubility of phosphate analogues 3m and 4g suggest their use as potential pro-drugs.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Péptidos/síntesis química , Péptidos/farmacología , Alquilación/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/crecimiento & desarrollo , Péptidos y Proteínas de Señalización Intercelular , Pruebas de Sensibilidad Microbiana/estadística & datos numéricos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/crecimiento & desarrolloRESUMEN
In water, the rate of Michael addition of amines and thiols to dehydroalanine amides was greatly accelerated, leading to shorter reaction times and higher yields. The scope of the new conditions was tested with a range of amines, thiols, and dehydroalanine amides. The ease and efficiency of this method provides an attractive route to the synthesis of natural and unnatural amino acid derivatives.
Asunto(s)
Alanina/análogos & derivados , Amidas/química , Aminas/química , Compuestos de Sulfhidrilo/química , Cinética , Agua/químicaRESUMEN
A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.