RESUMO
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.
Assuntos
Disponibilidade Biológica , Desenho de Fármacos , Relação Estrutura-Atividade , Antivirais/farmacocinética , Química Farmacêutica , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C , Estrutura Molecular , RNA Polimerase Dependente de RNA , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
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).
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Piridazinas/síntese química , Piridazinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Estrutura Molecular , Piridazinas/química , Relação Estrutura-AtividadeAssuntos
RNA Bacteriano/química , Ribossomos/química , 2-Aminopurina/química , Aminoglicosídeos/síntese química , Antibacterianos/síntese química , Cristalização , Cristalografia por Raios X , Marcação de Genes , Modelos Moleculares , Conformação de Ácido Nucleico , Oligonucleotídeos/química , RNA Bacteriano/biossíntese , RNA Bacteriano/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Espectrometria de Fluorescência , Espectrofotometria UltravioletaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Piperidinas/síntese química , Piperidinas/farmacologia , Aminoglicosídeos , Antibacterianos/farmacologia , Mimetismo Molecular , Biossíntese de Proteínas/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Alanina/análogos & derivados , Mimetismo Molecular , Tioestreptona/química , Alanina/síntese química , Cromatografia Líquida , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Tioestreptona/farmacologiaRESUMO
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.
Assuntos
Aminoglicosídeos/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Antibacterianos/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Desenho de Fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Piperidinas/farmacologia , Conformação Proteica , Ribossomos/efeitos dos fármacos , Relação Estrutura-Atividade , Triazinas/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Hexosaminas/química , Hexosaminas/farmacologia , RNA Ribossômico/metabolismo , Aminoglicosídeos , Sítios de Ligação , Luciferases/genética , Modelos Moleculares , Biossíntese de Proteínas/efeitos dos fármacos , RNA Ribossômico/efeitos dos fármacos , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacosRESUMO
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.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/farmacologia , RNA Ribossômico/antagonistas & inibidores , Aminoglicosídeos/química , Antibacterianos/química , Sítios de Ligação , Sistema Livre de Células , Desenho de Fármacos , Biossíntese de Proteínas/efeitos dos fármacos , RNA Bacteriano/antagonistas & inibidores , RNA Ribossômico/química , RNA Ribossômico/ultraestrutura , Relação Estrutura-AtividadeRESUMO
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.