RESUMO
DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)-C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.
Assuntos
DNA/química , Biblioteca Gênica , Modelos Moleculares , CinéticaRESUMO
Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel-Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.
Assuntos
Alcenos/química , Água/química , Catálise , Cobalto/química , Complexos de Coordenação/química , Ciclização , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , IsomerismoRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.
Assuntos
Aminas/síntese química , Benzamidas/síntese química , Biomarcadores Tumorais , Descoberta de Drogas , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Aminas/química , Aminas/farmacologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Compostos Macrocíclicos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
Assuntos
Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/química , Modelos Moleculares , Estrutura Molecular , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Compostos Macrocíclicos/química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Sítios de Ligação , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Ratos , Transplante HeterólogoRESUMO
A series of substituted benzo[c][2,7]-naphthyridines were prepared and showed good potency in inhibiting PDK-1. The synthesis and SAR of this series of compounds are presented as well as the X-ray crystal structure of one of these analogs in a complex with PDK-1.
Assuntos
Antineoplásicos/química , Naftiridinas/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Conformação Molecular , Naftiridinas/síntese química , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 4-indolylamino-5-phenyl-3-pyridinecarbonitrile inhibitors of PKCtheta were synthesized as potential anti-inflammatory agents. The effects of specific substitution on the 5-phenyl moiety and variations of the positional isomers of the 4-indolylamino substituent were explored. This study led to the discovery of compound 12d, which had an IC(50) value of 18nM for the inhibition of PKCtheta.
Assuntos
Isoenzimas/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Trifosfato de Adenosina/química , Animais , Anti-Inflamatórios/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Isoenzimas/química , Camundongos , Modelos Químicos , Estrutura Molecular , Isoformas de Proteínas , Proteína Quinase C/química , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody-drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.
Assuntos
Anticorpos Biespecíficos/administração & dosagem , Antígeno de Maturação de Linfócitos B/metabolismo , Complexo CD3/imunologia , Imunoconjugados/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Animais , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacologia , Afinidade de Anticorpos , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Camundongos , Mieloma Múltiplo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.
Assuntos
Inibidores da Angiogênese/síntese química , Benzoquinonas/síntese química , Quinazolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Benzoquinonas/química , Benzoquinonas/farmacologia , Sítios de Ligação , Linhagem Celular , Feminino , Glutationa/química , Humanos , Cinética , Camundongos , Camundongos Nus , Modelos Moleculares , Conformação Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Teoria Quântica , Quinazolinas/química , Quinazolinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The effect of introducing hydrophobic groups onto the disaccharide portion of the mannopeptimycins has been examined. Under acid-catalyzed conditions dimethyl acetals and ketals react on the terminal mannose of the disaccharide moiety of mannopeptimycin-alpha and the cyclohexylalanyl analogue 2. The preferentially formed monofunctionalized 4,6-acetals and -ketals display potent antibacterial activities against Gram-positive microorganisms, including MRSA, PRSP, and VRE pathogens.
Assuntos
Acetais/síntese química , Antibacterianos/síntese química , Glicopeptídeos , Bactérias Gram-Positivas/efeitos dos fármacos , Acetais/química , Acetais/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Reported here are procedures for a one-pot oxidation and rearrangement of propargylamines to synthesize enaminones, with supporting mechanistic studies. Also reported are the extended one-pot syntheses of pyrazoles, including celecoxib and various heterocyclic compounds.
Assuntos
Pargilina/análogos & derivados , Propilaminas/química , Pirazóis/síntese química , Sulfonamidas/síntese química , Catálise , Celecoxib , Técnicas de Química Combinatória , Estrutura Molecular , Oxirredução , Pargilina/química , Pirazóis/química , Sulfonamidas/químicaRESUMO
Antibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window.
Assuntos
Anticorpos/química , Antineoplásicos/química , Imunoconjugados/química , Animais , Anticorpos/imunologia , Meia-Vida , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias Leves de Imunoglobulina/química , Cadeias Leves de Imunoglobulina/imunologia , Camundongos , Neoplasias/tratamento farmacológico , Ratos , Transglutaminases/metabolismo , Moduladores de Tubulina/químicaRESUMO
A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Piridinas/química , Eletricidade Estática , Relação Estrutura-AtividadeRESUMO
A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Bioensaio , Células Cultivadas , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
ZipA is a membrane anchored protein in Escherichia coli that interacts with FtsZ, a homolog of eukaryotic tubulins, forming a septal ring structure that mediates bacterial cell division. Thus, the ZipA/FtsZ protein-protein interaction is a potential target for an antibacterial agent. We report here an NMR-based fragment screening approach which identified several hits that bind to the C-terminal region of ZipA. The screen was performed by 1H-15N HSQC experiments on a library of 825 fragments that are small, lead-like, and highly soluble. Seven hits were identified, and the binding mode of the best one was revealed in the X-ray crystal structure. Similar to the ZipA/FtsZ contacts, the driving force in the binding of the small molecule ligands to ZipA is achieved through hydrophobic interactions. Analogs of this hit were also evaluated by NMR and X-ray crystal structures of these analogs with ZipA were obtained, providing structural information to help guide the medicinal chemistry efforts.
Assuntos
Antibacterianos/síntese química , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Escherichia coli/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Complexos Multiproteicos/antagonistas & inibidores , Antibacterianos/farmacologia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Proteínas de Escherichia coli/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin alpha (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC(90)s], 0.03 to 0.06 microg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC(90)s, 0.12 and 0.25 microg/ml, respectively) as well as against streptococcal strains (MIC(90)s,
Assuntos
Antibacterianos/farmacologia , Glicopeptídeos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Humanos , Cinética , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/farmacologiaRESUMO
A series of ester and carbonate derivatives of the glycopeptide mannopeptimycin alpha (1) with potent activity against G+ bacteria, including the methicillin-resistant staphylococci and vancomycin-resistant enterococci, was synthesized. The SAR data obtained from natural and semisynthetic compounds demonstrated the importance of a hydrophobic group in the terminal mannosyl moiety for antibacterial activity.
Assuntos
Antibacterianos/química , Carbonatos/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Glicopeptídeos , Animais , Antibacterianos/farmacologia , Carbonatos/farmacologia , Farmacorresistência Bacteriana Múltipla/fisiologia , Ésteres , Camundongos , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C(55)-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Resistência a Vancomicina , Marcadores de Afinidade , Antibacterianos/metabolismo , Proteínas da Membrana Bacteriana Externa , Proteínas de Bactérias/metabolismo , Ligação Competitiva/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cromatografia em Camada Fina , Meios de Cultura , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli , Glicopeptídeos , Bactérias Gram-Positivas/metabolismo , Hexosiltransferases/metabolismo , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às Penicilinas , Peptidoglicano/biossíntese , Peptidil Transferases/metabolismo , Ligação Proteica , Receptores Virais , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
A series of highly potent thiourea inhibitors of cytomegalovirus (CMV) with improved stability properties was prepared and evaluated. Compound 29 inhibited the virus in cultured HFF cells with IC50 of 0.2 nM.