RESUMEN
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Asunto(s)
Disponibilidad Biológica , Diseño de Fármacos , Relación Estructura-Actividad , Antivirales/farmacocinética , Química Farmacéutica , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C , Estructura Molecular , ARN Polimerasa Dependiente del ARN , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Hepacivirus/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacocinética , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/sangre , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Piridazinas/sangre , Piridazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Tiazoles/síntesis química , Tiofenos/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Genotipo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , ARN Viral/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiofenos/farmacocinéticaAsunto(s)
ARN Bacteriano/química , Ribosomas/química , 2-Aminopurina/química , Aminoglicósidos/síntesis química , Antibacterianos/síntesis química , Cristalización , Cristalografía por Rayos X , Marcación de Gen , Modelos Moleculares , Conformación de Ácido Nucleico , Oligonucleótidos/química , ARN Bacteriano/biosíntesis , ARN Bacteriano/efectos de los fármacos , Ribosomas/efectos de los fármacos , Espectrometría de Fluorescencia , Espectrofotometría UltravioletaRESUMEN
Aminoglycoside antibiotics target an internal RNA loop within the bacterial ribosomal decoding site. Here, we describe the synthesis and SAR of novel 3,5-diamino-piperidine derivatives as aminoglycoside mimetics, and show they act as inhibitors of bacterial translation and growth.
Asunto(s)
Antibacterianos/síntesis química , Piperidinas/síntesis química , Piperidinas/farmacología , Aminoglicósidos , Antibacterianos/farmacología , Imitación Molecular , Biosíntesis de Proteínas/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
Syntheses of dehydroalanine derivatives via a solid-support route, starting from selenocystein, and via conventional solution phase chemistry are described along with initial biological testing. The target compounds were designed as mimetics of the dehydroalanine side chain of the macrocyclic antibiotic thiostrepton that acts on the bacterial ribosome.
Asunto(s)
Alanina/análogos & derivados , Imitación Molecular , Tioestreptona/química , Alanina/síntesis química , Cromatografía Liquida , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Tioestreptona/farmacologíaRESUMEN
We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.
Asunto(s)
Aminoglicósidos/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Antibacterianos/farmacología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Diseño de Fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Piperidinas/farmacología , Conformación Proteica , Ribosomas/efectos de los fármacos , Relación Estructura-Actividad , Triazinas/farmacologíaRESUMEN
The ribosomal decoding site is the target of aminoglycoside antibiotics that specifically recognize an internal loop RNA structure. We synthesized RNA-targeted 2,5-dideoxystreptamine-4-amides in which a sugar moiety in natural aminoglycosides is replaced by heterocycles.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Hexosaminas/química , Hexosaminas/farmacología , ARN Ribosómico/metabolismo , Aminoglicósidos , Sitios de Unión , Luciferasas/genética , Modelos Moleculares , Biosíntesis de Proteínas/efectos de los fármacos , ARN Ribosómico/efectos de los fármacos , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
Natural aminoglycoside antibiotics recognize an internal loop of bacterial ribosomal-decoding-site RNA by binding to the deep groove of the RNA structure. We have designed, synthesized, and tested RNA-targeted paromamine derivatives that exploit additional interactions on the shallow groove face of the decoding-site RNA. An in vitro transcription-translation assay of a series of 6'-derivatives showed the 6'-position to be very sensitive to substitution. This result suggests that the group at the 6'-position plays a pivotal role in RNA target recognition.
Asunto(s)
Aminoglicósidos/síntesis química , Aminoglicósidos/farmacología , ARN Ribosómico/antagonistas & inhibidores , Aminoglicósidos/química , Antibacterianos/química , Sitios de Unión , Sistema Libre de Células , Diseño de Fármacos , Biosíntesis de Proteínas/efectos de los fármacos , ARN Bacteriano/antagonistas & inhibidores , ARN Ribosómico/química , ARN Ribosómico/ultraestructura , Relación Estructura-ActividadRESUMEN
RNA recognition by natural aminoglycoside antibiotics depends on the 2-deoxystreptamine (2-DOS) scaffold which participates in specific hydrogen bonds with the ribosomal decoding-site target. Three-dimensional structure information has been used for the design of azepane-monoglycosides, building blocks for novel antibiotics in which 2-DOS is replaced by a heterocyclic scaffold. Azepane-glycosides showed target binding and translation inhibition in the low micromolar range and inhibited growth of Staphylococcus aureus, including aminoglycoside-resistant strains.