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1.
Comput Biol Chem ; 69: 171-177, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28391977

RESUMO

Construction of phylogenetic trees has traditionally focused on binary trees where all species appear on leaves, a problem for which numerous efficient solutions have been developed. Certain application domains though, such as viral evolution and transmission, paleontology, linguistics, and phylogenetic stemmatics, often require phylogeny inference that involves placing input species on ancestral tree nodes (live phylogeny), and polytomies. These requirements, despite their prevalence, lead to computationally harder algorithmic solutions and have been sparsely examined in the literature to date. In this article we prove some unique properties of most parsimonious live phylogenetic trees with polytomies, and their mapping to traditional binary phylogenetic trees. We show that our problem reduces to finding the most compact parsimonious tree for n species, and describe a novel efficient algorithm to find such trees without resorting to exhaustive enumeration of all possible tree topologies.


Assuntos
Algoritmos , Filogenia
2.
J Antibiot (Tokyo) ; 42(11): 1673-83, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2684947

RESUMO

Reductive amination of the C-20 aldehyde group of tylosin and related macrolides yielded a large series of derivatives with potentially useful antibiotic properties. Evaluation of these new compounds was conducted on the basis of: 1) Broad antimicrobial spectrum in vitro, with particular emphasis on inhibition of Pasteurella multocida and Pasteurella haemolytica; 2) in vivo efficacy, especially when given orally, against P. multocida in experimental infections in chicks; and 3) bioavailability after oral administration to laboratory animals. The most useful activity was found within a series of derivatives produced by reductive amination of desmycosin with secondary amines.


Assuntos
Pasteurella/efeitos dos fármacos , Tilosina/análogos & derivados , Aminação , Animais , Galinhas , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxirredução , Infecções por Pasteurella/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Tilosina/síntese química , Tilosina/farmacologia
3.
J Antibiot (Tokyo) ; 42(8): 1253-67, 1989 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2668243

RESUMO

A series of 20-deoxo-20-cyclic (alkylamino) derivatives of tylosin, desmycosin, macrocin and lactenocin was prepared by reductive amination of the C-20 aldehyde group. The majority of the compounds were prepared using metal hydrides (sodium cyanoborohydride or sodium borohydride) as the reducing agents and a suitable cyclic alkylamine. Subsequently, a more convenient procedure was developed using formic acid as a reducing agent. The C-20 amino derivatives prepared from desmycosin exhibited good in vitro antimicrobial activity against Pasteurella haemolytica and Pasteurella multocida (MIC range of 0.78 approximately 6.25 micrograms/ml) as well as Mycoplasma species (MIC range of 0.39 approximately 6.25 micrograms/ml). Several derivatives showed excellent oral efficacy against infections caused by P. multocida in chicks. One of these derivatives, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin or EL-870) was selected for development as a therapeutic agent for pasteurellosis in calves and pigs.


Assuntos
Antibacterianos , Leucomicinas/síntese química , Macrolídeos , Tilosina/análogos & derivados , Aminação , Animais , Galinhas , Leucomicinas/farmacologia , Leucomicinas/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycoplasma/efeitos dos fármacos , Oxirredução , Pasteurella/efeitos dos fármacos , Infecções por Pasteurella/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes
4.
J Antibiot (Tokyo) ; 42(1): 63-72, 1989 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2921228

RESUMO

Over eighty N-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The N-alkyl vancomycins exhibit greater antibacterial activity than the corresponding N-acyl vancomycins and the parent antibiotic. Some of these semisynthetic vancomycins are five times more active than vancomycin. The N-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.


Assuntos
Vancomicina/análogos & derivados , Animais , Ratos , Relação Estrutura-Atividade , Vancomicina/síntese química , Vancomicina/farmacologia
5.
J Antibiot (Tokyo) ; 41(10): 1430-8, 1988 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3192496

RESUMO

Several glycopeptides containing N-acyl groups have been isolated recently. We undertook the synthesis of N-acyl vancomycins, using the active ester method. The in vitro and in vivo antibacterial activity were evaluated, and structure-activity relationship of this series of semisynthetic vancomycins is discussed.


Assuntos
Vancomicina/análogos & derivados , Animais , Infecções Bacterianas/tratamento farmacológico , Fenômenos Químicos , Química , Técnicas In Vitro , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Vancomicina/síntese química
6.
J Med Chem ; 31(10): 1987-93, 1988 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3172134

RESUMO

A number of 7-(arylacetamido)-3-substituted cephalosporins were prepared and tested in animals for oral absorbability. Bioavailability in mice, rats, dogs, and monkeys was determined after oral or parenteral administration. Oral bioavailability of five compounds selected for more intensive study was generally higher than that of penicillin V in all species tested. The results of ED50 testing against experimental infections in mice generally supported the bioavailability studies. Antibiotic activities were evaluated against Gram-positive and Gram-negative organisms with some derivatives expressing in vitro activity similar to cefaclor. The plasma half-life in rats was relatively short and the plasma curves were strongly influenced by probenecid, indicating rapid renal secretion. Some 7-(arylacetamido)-3-chloro cephalosporins are orally absorbed in animals to a greater extent than penicillin V, and antibacterial agent of proven clinical utility.


Assuntos
Cefalosporinas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cefalosporinas/sangue , Cefalosporinas/síntese química , Cães , Macaca mulatta , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Ratos Endogâmicos
7.
J Med Chem ; 31(10): 1993-7, 1988 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3172135

RESUMO

The structure-activity relationship for 7-arylacetamido cephalosporins has been extended. Modifications of the 7-aryl group led to improvements in microbiological activity against Gram-positive organisms. However, Gram-negative activity was generally much poorer than that of the lead compound 7-[(2-aminothiazol-4-yl)acetamido]-3-chloro-cephalosporanic acid (A). Modifications of the 3-position did not significantly change the microbiological activity or spectrum. Of the compounds selected for mouse protection studies (ED50's), 7-[(benzothien-3-yl)acetamido]-3-chloro cephalosporin and A showed the best per oral to subcutaneous ED50 ratios.


Assuntos
Cefalosporinas/farmacocinética , Administração Oral , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Disponibilidade Biológica , Cefalosporinas/sangue , Cefalosporinas/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
8.
J Med Chem ; 31(8): 1631-41, 1988 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-3398001

RESUMO

Modification of the aldehyde group in tylosin and related macrolide antibiotics dramatically enhanced the oral efficacy of the derivatives against experimental infections caused by susceptible bacteria in laboratory animals. A large number and wide variety of aldehyde-modified macrolide derivatives were prepared, utilizing the Mitsunobu reaction and other chemical transformations. Evaluation of in vitro and in vivo antimicrobial activity indicated that derivatives of demycarosyltylosin (desmycosin) combined the broadest spectrum of antimicrobial activity with the best efficacy and bioavailability after oral administration.


Assuntos
Leucomicinas/síntese química , Administração Oral , Aldeídos/síntese química , Aldeídos/farmacocinética , Aldeídos/farmacologia , Animais , Bactérias Anaeróbias/efeitos dos fármacos , Disponibilidade Biológica , Fenômenos Químicos , Química , Leucomicinas/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Staphylococcus/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Relação Estrutura-Atividade
9.
J Antibiot (Tokyo) ; 41(8): 1093-105, 1988 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2844711

RESUMO

The novel lipopeptide antibiotic A21978C complex is active against Gram-positive organisms. This complex consists of a common peptide nucleus with various lipid acyl groups at the N-terminus characteristic of each individual factor. The fatty acid acyl group is removed by incubation of the A21978C complex with Actinoplanes utahensis to give the peptide nucleus. This peptide nucleus has the same amino acid sequence as A21978C. New analogs of A21978C were synthesized by acylation of the N-terminus of a tert-butoxycarbonyl (tert-BOC)-protected nucleus and subsequent deprotection. 1H NMR showed that the newly introduced acyl group was at the desired N-terminus. Three major groups of analogs were synthesized bearing fatty acid acyl, amino-aroyl and extended peptide side chains. Each analog was evaluated for antimicrobial activity and acute toxicity. Of these analogs, the n-decanoyl analog of A21978C (LY146032) gave the best survival in the mouse acute toxicity test at a high dose of 1,000 mg/kg, iv and was chosen for further study. This analog has been named daptomycin.


Assuntos
Antibacterianos , Antibacterianos/biossíntese , Actinomycetales/metabolismo , Acilação , Sequência de Aminoácidos , Animais , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Fenômenos Químicos , Química , Daptomicina , Fermentação , Peptídeos e Proteínas de Sinalização Intercelular , Lipídeos/análise , Camundongos , Testes de Sensibilidade Microbiana , Biossíntese Peptídica , Peptídeos/análise , Peptídeos/farmacologia , Peptídeos/toxicidade , Peptídeos Cíclicos/biossíntese , Peptídeos Cíclicos/toxicidade , Ratos , Streptomyces/metabolismo , Relação Estrutura-Atividade
10.
J Antibiot (Tokyo) ; 40(6): 823-42, 1987 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3610835

RESUMO

A large series of C-23-modified derivatives of 5-O-mycaminosyltylonolide were synthesized, in which the C-23 hydroxyl group was replaced by halo, aryl ether or thioether, azido, amino or dialkylamino substituents via SN2 displacement reactions. The majority of derivatives possessed excellent in vitro activity against a variety of aerobic and anaerobic bacteria. While some of the compounds treated experimental infections in rodents by parenteral administration, none showed any significant efficacy or bioavailability after oral dosing. Novel rearrangement products were obtained from some of the reactions; these were identified as 13,23-cyclopropyl-12,22-exomethylene and 13,23-cyclopropyl-12-alkoxy derivatives.


Assuntos
Leucomicinas , Leucomicinas/síntese química , Animais , Infecções Bacterianas/tratamento farmacológico , Fenômenos Químicos , Química , Cães , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Leucomicinas/farmacologia , Leucomicinas/uso terapêutico , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-Atividade
12.
J Antibiot (Tokyo) ; 39(8): 1108-22, 1986 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-3759662

RESUMO

A large number and wide variety of acyl derivatives of the tylosin-related macrolides 23-demycinosyltylosin (DMT), 23-demycinosyloxytylosin (DMOT) and 5-O-mycaminosyltylonolide (OMT) were synthesized and evaluated. This encompassed conversion of the hydroxyl groups at 2',4' and 23 of the appropriate macrolides to the corresponding esters, in which a variety of different substitution patterns were examined. A wide range of acyl substituents was investigated, particularly for 23-O-acyl derivatives of OMT, since these were substantially more active in vitro than OMT itself. However, the acyl derivatives which were prepared demonstrated no substantial improvement in oral efficacy or bioavailability over the parent macrolides.


Assuntos
Leucomicinas/síntese química , Acilação , Animais , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Leucomicinas/sangue , Leucomicinas/farmacologia , Camundongos , Relação Estrutura-Atividade
13.
Antimicrob Agents Chemother ; 29(5): 774-80, 1986 May.
Artigo em Inglês | MEDLINE | ID: mdl-3729340

RESUMO

MICs of a set of cephalosporins against a variety of gram-positive and gram-negative pathogens showed no strong correlations with the rate at which these inhibitors acylate or are deacylated by beta-lactam-sensitive DD-peptidases excreted by Streptomyces sp. strain R61 and Actinomadura sp. strain R39.


Assuntos
Carboxipeptidases/antagonistas & inibidores , Cefalosporinas/farmacologia , Muramilpentapeptídeo Carboxipeptidase/antagonistas & inibidores , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Cinética , Testes de Sensibilidade Microbiana
14.
J Antibiot (Tokyo) ; 39(2): 281-5, 1986 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3485626

RESUMO

Recent work has shown that the activity of cephalosporins in inhibiting exocellular DD-peptidases from Streptomyces R61 and Actinomadura R39 are, at best, only poorly related to minimum inhibitory concentrations against pathogenic isolates. Taking into account the rate at which cephalosporins diffuse through porin channels, such as exist in certain Gram-negative organisms, does not help in establishing a relationship between MIC data and the kinetic data on the model enzymes. Most published cell wall permeability studies, the porin ones being a principal exception, have not examined long enough series of structurally related compounds to establish property-activity relationships.


Assuntos
Aciltransferases/antagonistas & inibidores , Permeabilidade da Membrana Celular , Cefalosporinas/farmacologia , Peptidil Transferases/antagonistas & inibidores , Antibacterianos/farmacologia , Cefalosporinas/metabolismo , Cinética , Testes de Sensibilidade Microbiana , Modelos Biológicos , Relação Estrutura-Atividade , beta-Lactamases/análise
15.
J Med Chem ; 28(12): 1903-6, 1985 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2933520

RESUMO

The methyl and isopropyl esters of (RS)-3-benzothienylglycine were resolved with (+)- and (-)-tartaric acid in acetonitrile to give the corresponding R and S salts. The R-salt 4 was hydrolyzed to (R)-3-benzothienylglycine (5). The amino group in 5 was protected with the Boc function and the protected R amino acid 6 coupled with the p-NB ester of 7-ADCA to give the diprotected cephalosporin 7. After removal of the Boc and p-NB groups, the R isomer of 7-(3-benzothienylglycylamido)deacetoxycephalosporanic acid (1) was obtained. The p-NB ester of epimeric cephalosporin 7 was separated by preparative chromatography into R and S isomers. After removal of the protective groups, the S epimer was isolated. The comparison of antibacterial activity of the R and S epimers and the RS mixture of cephalosporin 1 is reported.


Assuntos
Cefalosporinas/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Administração Oral , Cefalosporinas/isolamento & purificação , Cefalosporinas/farmacologia , Fenômenos Químicos , Química , Glicina/análogos & derivados , Haemophilus influenzae/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos , Estereoisomerismo , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos
16.
J Med Chem ; 28(12): 1896-903, 1985 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3877809

RESUMO

Three positional analogues (4-, 5-, and 7-) of benzothienylglycine and (N-acetylindolinyl)-5-glycine were prepared and coupled to 7-aminodeacetoxycephalosporanic acid (7-ADCA) to give the cephalosporins 17a-c. In addition two isomeric (2,3-b and 3,2-b) thienothiopheneglycines were synthesized and coupled to 7-ADCA to yield cephalosporins 30d and 30e. In vitro testing of these new cephalosporins indicates good activity against Gram-positive bacteria. Against Streptococcus pneumoniae infections compound 25 displayed better mouse protection (both orally and subcutaneously) than cephalexin.


Assuntos
Cefalosporinas/farmacologia , Glicina/análogos & derivados , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Tiofenos/farmacologia , Administração Oral , Animais , Cefalexina/farmacologia , Cefalexina/uso terapêutico , Cefalosporinas/síntese química , Fenômenos Químicos , Química , Glicina/síntese química , Glicina/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Indóis/síntese química , Indóis/uso terapêutico , Camundongos , Infecções Pneumocócicas/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos/síntese química
17.
J Antibiot (Tokyo) ; 35(12): 1675-82, 1982 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7166533

RESUMO

Although a substantial number of 16-membered macrolides related to tylosin have now been isolated and evaluated as antibiotics, none appeared to be superior to tylosin in treating bacterial or mycoplasmal infections caused by sensitive organisms. Nevertheless, this comparison of the antibiotic activity of 16-membered macrolides clearly indicates that novel antibiotics with potentially useful activity can be obtained from mutant strains which have been blocked at various steps in their biosynthesis of antimicrobial agents. The novel compounds thus produced may also be used as starting materials for additional chemical and microbiological modification. Furthermore, the mutant strains which produced these novel compounds should be useful recipients for interspecific genetic recombination by protoplast fusion or gene cloning to yield hybrid antibiotics. Even greater exploitation of these methods will be required in the continuing search for new antibiotics and improved methods for producing them.


Assuntos
Leucomicinas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Galinhas , Leucomicinas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mycoplasma/efeitos dos fármacos , Infecções por Mycoplasma/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Relação Estrutura-Atividade
19.
Antimicrob Agents Chemother ; 15(1): 14-9, 1979 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-311615

RESUMO

A large number of cultures of gram-negative bacteria were examined for their susceptibility to various concentrations of cefamandole, cefoxitin, carbenicillin, and nalidixic acid. Heterogeneity of susceptibility was demonstrated in individual cultures to all of these antibiotics. Resistant clones isolated from cefamandole or cefoxitin plates were examined for beta-lactamase production. Approximately 13% of 262 resistant clones acquired the ability to produce a beta-lactamase. Examination of the substrate profile of the beta-lactamases from some of these clones revealed no change in the specific activity of these enzymes for cefamandole, cephaloridine, or compound 87/312 as compared with their parental enzymes. This study clearly shows that some resistant clones do not produce beta-lactamases, whereas some susceptible strains produced significant amounts of these enzymes. We conclude from these findings that little correlation exists between beta-lactamase production and decreased susceptibility to cefamandole or cefoxitin. The results suggest the possibility that characteristics other than beta-lactamase production may be responsible for resistance in Enterobacteriaceae.


Assuntos
Cefamandol/farmacologia , Cefoxitina/farmacologia , Cefalosporinas/farmacologia , Enterobacteriaceae/efeitos dos fármacos , beta-Lactamases/biossíntese , Resistência Microbiana a Medicamentos , Enterobacteriaceae/enzimologia , Mutação
20.
J Med Chem ; 18(10): 986-92, 1975 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-808607

RESUMO

3-(Substituted)vinylcephem nuclei have been prepared by the reaction of 3-formylcephem derivatives with stabilized phosphoranes. Appropriate synthetic steps allowed preparation of a series of 3-ethoxycarbonylvinyl- and 3-carboxyvinylcephem derivatives bearing a variety of 7-acylamino functions. The phenoxyacetyl and thiopheneacetyl derivatives of the 3-cyanovinylcephem nucleus were also prepared. Although general gram-positive activity was comparable to cephalothin in many cases, against penicillin G resistant Staphylococcus aureus, the new cephalosporins were of low effectiveness. The 3-(substituted)vinyl cephalosporins had good activity against a number of gram-negative organisms. In some cases, this activity was excellent. The N-acetyl analogs had surprisingly good activity relative to N-acetyl-7-ACA. The phenylmalonoyl side-chain derivatives were shown to have an unusual antibacterial spectrum expansion (relative to previously known cephalosporins) to include activity against Serratia marcescens and Pseudomonas aeruginosa.


Assuntos
Cefalosporinas/síntese química , Bacillus subtilis/efeitos dos fármacos , Cefalosporinas/farmacologia , Enterobacter/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Sarcina/efeitos dos fármacos , Serratia marcescens/efeitos dos fármacos , Shigella/efeitos dos fármacos , Espectrofotometria Ultravioleta , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Compostos de Vinila/síntese química , Compostos de Vinila/farmacologia
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