RESUMO
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 µM in a combination 3'-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 µM.
Assuntos
Desenho de Fármacos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Tirosina/química , Integrase de HIV/química , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure-activity relationships of these inhibitors, which show potential as antibacterial agents.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Imidazóis/química , Pirazinas/química , Antibacterianos/síntese química , Antibacterianos/metabolismo , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Bactérias Gram-Negativas/metabolismo , Imidazóis/síntese química , Imidazóis/metabolismo , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Pirazinas/síntese química , Pirazinas/metabolismo , Relação Estrutura-AtividadeRESUMO
A compact synthesis of 15 new binaphthyl-based dicationic tripeptoids and one biphenyl based dicationic tripeptoid is described. Fourteen of these tripeptoids resulted from variation of the C-2' ether substituent of the binaphthyl unit. An O-iso-butyl ether binaphthyl derivative was found to be the most active against Staphylococcus aureus (MIC 1.95 µg/mL). The biphenyl analogue also showed good activity against S. aureus (MIC 1.95 µg/mL). These compounds, however, were less active against four vancomycin-resistant strains of enterococci (VRE) than some of our previously developed compounds that had an O-iso-pentyl ether substituent on the binaphthyl unit and a C-2 L-Leu moiety.
Assuntos
Antibacterianos/síntese química , Naftalenos/química , Peptoides/química , Antibacterianos/química , Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Peptoides/síntese química , Peptoides/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Resistência a VancomicinaRESUMO
An efficient synthesis of 29 new binaphthyl-based neutral, and mono- and di-cationic, peptoids is described. Some of these compounds had antibacterial activities with MIC values of 1.9-3.9microg/mL against Staphylococcus aureus. One peptoid had a MIC value of 6microg/mL against a methicillin-resistant strain of S. aureus (MRSA) and a MIC value of 2microg/mL against vancomycin-resistant strains of enterococci (VRE).
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Cromatografia Líquida de Alta Pressão , Enterococcus/efeitos dos fármacos , Indicadores e Reagentes , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Resistência a VancomicinaRESUMO
QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (-)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the beta subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Inibidores da Topoisomerase II , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Área Sob a Curva , Bactérias/enzimologia , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Taxa de Depuração Metabólica , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , EstereoisomerismoRESUMO
An efficient synthesis of two new N-acetyl-4'-arylphenylalanines is described together with their incorporation into a number of cationic peptoid antibacterial agents, one of which had an MIC of 7.8 microg/mL against Staphylococcus aureus.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Fenilalanina/síntese química , Fenilalanina/farmacologia , Antibacterianos/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Fenilalanina/química , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacosRESUMO
Screening of our compound collection identified PNU-92560, a 2-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide, as a novel antibacterial agent. Extensive analogue development identified that the 2-position of the thiadiazole could be functionalized with a linker that would allow the compound to be attached to a solid support. The extreme insolubility of the analogues prevented the mechanism of action for these compounds to be determined utilizing traditional methodology. The solid-supported compounds were utilized as affinity columns to identify elongation factor Tu (EF-Tu) as a putative target for this class of compounds. The activity of the compounds in a metabolic labeling experiments and in translation assay supports the identity of the target for these compounds to be EF-Tu.