5-Benzyl-2,4-diaminopyrimidines as Antibacterial Agents. I. Synthesis and Antibacterial Activity <i>in vitro</i>

Roth, Barbara; Falco, Elvira A.; Hitchings, George H.; Bushby, S. R. M.

doi:10.1021/jm01241a004

Cited by 134 publications

(52 citation statements)

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“…It has an antibacterial activity which has been established since it was first described by Roth, Falco, Hitchings, and Bushby (1962) and its use in this field is gaining in popularity with the advent of more recent studies (Drew, Hughes, Fowle, and Cassell, 1967a;Darrell, Garrod, and Waterworth, 1968).…”

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confidence: 99%

A haematological study of patients receiving long-term treatment with trimethoprim and sulphonamide

1970

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The haematological effects of long-term treatment for three months with a combination of trimethoprim and sulphamethoxazole were studied in 10 cases of chronic bronchitis. Trimethoprim selectively inhibits dihydrofolate reductase in bacteria but not in man. Only minor effects on folate metabolism were observed in nine cases, causing no clinical concern. Some degree of thrombocytopenia occurred in the tenth case which improved when folinic acid was given.

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confidence: 99%

A haematological study of patients receiving long-term treatment with trimethoprim and sulphonamide

1970

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“…The species that have least h ogy with the gonococcus (N. flavescens a catarrhalis) are also those that appear to from the gonococcus in the parameters ( ined in this study. The (6,25). Therefore, several trimethoprim analogs were examined to determine whether their affinity for N. gonorrhoeae dihydrofolate reductase would be sensitive to substitution on the benzyl moiety.…”

Section: Methodsmentioning

confidence: 99%

Dihydrofolate Reductase from Neisseria sp

Averett

Roth

Burchall

et al. 1979

Antimicrob Agents Chemother

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Members of the genus Neisseria are relatively nonsusceptible to trimethoprim, an inhibitor of dihydrofolate reductase. For example, the minimal inhibitory concentration (MIC) of trimethoprim for N. gonorrhoeae ranges from 2 to 70 ,ug/ ml, whereas the MIC for Escherichia coli is 0.2 ,ig/ml or less. In an effort to understand this difference, dihydrofolate reductase was partially purified from five Neisseria species and compared with the enzyme from E. coli. N. gonorrhoeae dihydrofolate reductase was similar to that from E. coli in molecular weight (18,000) and affinity for the substrates reduced nicotinamide adenine dinucleotide phosphate and dihydrofolate (Km = 13 and 8 ,uM, respectively). However, the gonococcal enzyme had a decreased affinity for trimethoprim, with an apparent K, of 45 x 10-9 M, some 30-fold greater than the E. coli value of 1.2 x 109 M. These enzymes also differed in their isoelectric points and pH activity profiles. Within the genus Neisseria, the dihydrofolate reductase isolated from N. meningitidis and N. lactamica resembled the N. gonorrhoeae enzyme, and only small differences were detected for the N. flavescens and Branhamella catarrhalis dihydrofolate reductases. These data indicate that the relatively poor affinity of trimethoprim for the dihydrofolate reductase from these organisms may be largely responsible for the relative nonsusceptibility of Neisseria sp. to trimethoprim. The contribution of other resistance mechanisms to the overall nonsusceptibility was assessed. Strains of N. gonorrhoeae with altered cell envelope permeability had MIC values less than twofold different from those of isogenic wild-type strains. Also, a direct relationship was observed between the affinity of trimethoprim analogs for gonococcal dihydrofolate reductase and the MIC of these compounds for the gonococcus. These observations suggest that the cell envelope of N. gonorrhoeae is not impermeable to trimethoprim. Changes in the amount of dihydrofolate reductase activity could cause alterations in the susceptibility of the gonococcus to trimethoprim, as demonstrated with N. gonorrhoeae strains selected for trimethoprim resistance after chemical mutagenesis. However, the level of dihydrofolate reductase activity in wild-type N. gonorrhoeae was similar to that of E. coli, indicating that the difference in the susceptibility of these organisms is not due to greater amounts of enzyme in N. gonorrhoeae.

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“…Considerando-se que a associação sulfametoxazol + trimetoprim reune, em proporção comprovadamente óti ma, dois blogueadores da síntese de folatos, de forma a obter um novo agente antim icrobiano mais potente que seus componen tes individualmente (7,18) (10) obtiveram dois bons resultados com a associação do trimetoprim à sulfadoxina em casos previamente sulfa-resistentes, em que houvs cicatrização das lesões tegumentares e melhora do processo pulmonar acompanhada de baixa dos títulos soroló-gicos. Em um terceiro caso referem também negativação sorológica, e em um quarto caso não houve qualquer melhora, vindo o paciente a falecer posteriormente.…”

Section: Acentuando a Necessidade Da Continuação Das Pesquisas Terapêunclassified

Emprego da associação sulfametoxazol + trimetoprim no tratamento da paracoccidioidose (blastomicose Sul-Americana)

Pedrosa¹,

Wanke²,

Coura³

1974

Rev. Soc. Bras. Med. Trop.

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Acentuando a necessidade da continuação das pesquisas terapêuticas em INTRODUÇÃODesde 1940, quando Ribeiro (17) intro duziu os derivados sulfamídicos na tera pêutica da paracoccidioidose, nenhum ou tro avanço comparável foi até o momento obtido. Apesar da descoberta e emprego clí nico de diversas outras drogas, entre as quais se destaca a anfotericina B, os deri vados sulfamídicos permanecem como pri meira escolha em seu tratam ento. Através de constantes aperfeiçoamentos que os tor naram cada vez menos tóxicos e de mais fácil administração, consolidou-se o seu va lor, passados mais de 30 anos (2,8,11,12,13,16). Entretanto, são conhecidos casos de sulfa-resistência, sejam primários ou ta r dios, estes últimos conseqüentes quer a tra tam ento insuficiente em dose ou tempo, quer a seleção de cepas resistentes'. Macha do Filho e M iranda (14) referem 17 casos de sulfa-resistência em 394 tratados, e Lo pes e Armond (10) 12 casos em 122 tra ta dos com diversos derivados sulfamídicos, entre outros autores (1,3,4,6,19,20), res saltando o problema terapêutico destes ca sos. Até recentemente a única opção para estes pacientes era o emprego da anfoteri cina B. Numerosos autores que a emprega ram

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5-Benzyl-2,4-diaminopyrimidines as Antibacterial Agents. I. Synthesis and Antibacterial Activity in vitro

Cited by 134 publications

References 1 publication

A haematological study of patients receiving long-term treatment with trimethoprim and sulphonamide

A haematological study of patients receiving long-term treatment with trimethoprim and sulphonamide

Dihydrofolate Reductase from Neisseria sp

Emprego da associação sulfametoxazol + trimetoprim no tratamento da paracoccidioidose (blastomicose Sul-Americana)

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