RESUMO
The synthesis and antibacterial activity of oxazolidinones containing dihydro-1,2-oxazine and 2-pyrazoline ring systems are described. Linezolid analogs utilizing dihydro-1,2-oxazines as morpholine mimics were prepared utilizing a nitrosoamine/diene 4+2 cycloaddition strategy. Pyrazolidine, hexahydro-pyridazine, and 2-pyrazoline analogs more closely related to eperezolid were also prepared. The most active of these new oxazolidinones were the dihydro-1,2-oxazine 6 and the 2-pyrazoline 20 both of which had potency similar to linezolid against a panel of Gram-positive bacteria.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Animais , Bactérias Gram-Positivas/efeitos dos fármacos , Linezolida , Camundongos , Testes de Sensibilidade MicrobianaRESUMO
Nocathiacin I (1) was converted to its deoxy indole analogue, nocathiacin II (2), another natural product, by a unique and facile chemical process. This process was applied to nocathiacin IV (4), generating the lactone analogue of glycothiohexide alpha (5), which was also prepared from nocathiacin II by a mild hydrolytic process. In contrast to glycothiohexide alpha (3), this lactone analogue (5) was found to exhibit in vivo antibacterial efficacy in an animal (mouse) infection model.
Assuntos
Antibacterianos/química , Peptídeos Cíclicos/química , Peptídeos/química , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Peptídeos/síntese química , Compostos de Sulfidrila/síntese química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Feminino , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Compostos de Sulfidrila/farmacologiaRESUMO
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.
Assuntos
Antibacterianos , Peptídeos , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/síntese química , Peptídeos/síntese química , Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular , Testes de Sensibilidade Microbiana , Peptídeos/farmacologia , Solubilidade , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-Atividade , Água/químicaRESUMO
BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was approximately 7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Animais , Antivirais/farmacocinética , Área Sob a Curva , Benzimidazóis/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Sigmodontinae , Proteínas Virais de Fusão/antagonistas & inibidoresRESUMO
BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.
Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Mapeamento Cromossômico , Clonagem Molecular , DNA Complementar/genética , Farmacorresistência Viral , Genótipo , Células Gigantes/patologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/genética , Temperatura , Proteínas Virais de Fusão/biossíntese , Ensaio de Placa Viral , Proteínas Virais/biossínteseRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Alquilação/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimentoRESUMO
Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Animais , Antifúngicos/farmacocinética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Estabilidade de Medicamentos , Feminino , Humanos , Indicadores e Reagentes , Infusões Intravenosas , Camundongos , Camundongos Endogâmicos ICR , Pró-Fármacos/farmacocinética , Ratos , Solubilidade , Relação Estrutura-Atividade , Sobrevida , Tiazóis/farmacocinética , Triazóis/farmacocinéticaRESUMO
Thiazolyl peptide antibiotics, nocathiacin I, II and III, were identified in a culture of Nocardia sp. WW-12651 (ATCC 202099). They exhibit potent in vitro activity (ng/ml) against a wide spectrum of gram-positive bacteria, including multiple-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Enterococcus faecium (MREF) and fully penicillin-resistant Streptococcus pneumoniae (PRSP), and demonstrate excellent in vivo efficacy in a systemic Staphylococcus aureus infection mice model.
Assuntos
Antibacterianos/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Nocardia/química , Peptídeos , Animais , Antibacterianos/química , Antibacterianos/classificação , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Fermentação , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nocardia/classificaçãoRESUMO
The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a beta-lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC(90)s) of 4, 2, and 8 microg/ml for methicillin-resistant strains of S. aureus, S. epidermidis, and S. haemolyticus, respectively, as determined on plates with Mueller-Hinton agar and 2% NaCl. The BMS-247243 MICs for MRSA were minimally affected by the susceptibility testing conditions (inoculum size, prolonged incubation, addition of salt to the test medium) or by staphylococcal beta-lactamases. BMS-247243 MIC(90)s for methicillin-susceptible staphylococcal species ranged from < or = 0.25 to 1 microg/ml. The BMS-247243 MIC(90) for beta-lactamase-producing S. aureus strains was fourfold higher than that for beta-lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococcal beta-lactamases at 4.5 to 26.2% of the rates measured for cephaloridine. The affinity of BMS-247243 for PBP 2a was >100-fold better than that of methicillin or cefotaxime. BMS-247243 is bactericidal for MRSA, killing the bacteria twice as fast as vancomycin. These in vitro activities of BMS-247243 correlated with its in vivo efficacy against infections in animals, including the neutropenic murine thigh and rabbit endocarditis models involving MRSA strains. In conclusion, BMS-247243 has in vitro and in vivo activities against methicillin-resistant staphylococci and thus may prove to be useful in the treatment of infections caused by these multidrug-resistant organisms.
Assuntos
Proteínas de Bactérias , Proteínas de Transporte , Resistência a Meticilina/fisiologia , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Muramilpentapeptídeo Carboxipeptidase , Piridinas/farmacologia , Piridinas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Ciclofosfamida/farmacologia , Endocardite Bacteriana/tratamento farmacológico , Endocardite Bacteriana/microbiologia , Hexosiltransferases/genética , Hexosiltransferases/metabolismo , Hidrólise , Terapia de Imunossupressão , Imunossupressores/farmacologia , Cinética , Resistência a Meticilina/genética , Camundongos , Testes de Sensibilidade Microbiana , Morfolinas/metabolismo , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Músculo Esquelético/microbiologia , Proteínas de Ligação às Penicilinas , Peptidil Transferases/genética , Peptidil Transferases/metabolismo , Ligação Proteica , Piridinas/metabolismo , Coelhos , Infecções Estafilocócicas/microbiologia , Vancomicina/uso terapêuticoRESUMO
BMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium. BMS-247243 also inhibits many inherently vancomycin-resistant species (Leuconstoc, Lactobacillus, Pediococcus) and anaerobic gram-positive bacteria.