RESUMEN
The synthesis of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2-(1-normon-2-yl) oxazoles is described. The antibacterial activity was determined as the minimum inhibitory concentration against a range of Gram-positive and Gram-negative organisms using a standard Agar dilution procedure. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Mupirocina/química , Mupirocina/farmacología , Oxazoles/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia MagnéticaRESUMEN
A series of C-1 oxazole isosteres of pseudomonic acid A (mupirocin) bearing a nitroheterocycle have been synthesized, and significant differences in both spectrum of activity and potency were found between these derivatives and mupirocin. Additionally, the antibacterial potency of two members of this class of compounds against mupirocin-resistant staphylococci could not be accounted for solely by inhibition of the target enzyme isoleucyl-tRNA synthetase (IRS), indicating an additional mode of action. The most potent compound, the nitrofuran 3f (SB 205952), was the most electron affinic derivative prepared and was transformed by NAD(P)H-dependent bacterial reductases at a rate similar to that for nitrofurantoin. The second mode of action of this compound may therefore arise from its reduction to a species with cellular targets other than IRS. In in vivo studies, 3f was shown to be a very effective agent by both the subcutaneous and oral routes of administration.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Mupirocina/farmacología , Mupirocina/análogos & derivados , Relación Estructura-ActividadRESUMEN
The electronic requirements around the C1-C3 region of pseudomonic acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.
Asunto(s)
Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Isoleucina-ARNt Ligasa/antagonistas & inhibidores , Mupirocina/química , Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Mupirocina/análogos & derivados , Mupirocina/farmacología , Espectrofotometría Infrarroja , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Electricidad Estática , Relación Estructura-ActividadRESUMEN
The ketone (+/-)-5, which embodies the bicyclic core associated with the title tRNA synthetase inhibitors 1 and 2, has been prepared via a three-component coupling reaction involving 2-(hydroxymethyl)cyclopent-2-enone (15), methylamine (6) and propiolamide (10); straightforward elaboration of the readily derived acetates (-)-21 and (+)-21 has provided the biologically active analogues 23 and 24, respectively, of the title compounds.
Asunto(s)
Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Indenos/química , Sulfonamidas/química , Inhibidores Enzimáticos/farmacología , Indenos/farmacología , Sulfonamidas/farmacologíaRESUMEN
The structure-activity relationships within a series of penicillins and cephalosporins containing an N(4)-substituted piperazine-2,3-dione moiety in the C(6)/C(7)-beta-side chain are discussed.
Asunto(s)
Cefalosporinas/farmacología , Penicilinas/farmacología , Piperazinas/farmacología , Cefalosporinas/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Penicilinas/síntesis química , Piperazinas/síntesis química , Análisis Espectral , Relación Estructura-ActividadRESUMEN
The antimycoplasmal activities of the pseudomonic acids isolated from Pseudomonas fluorescens NCIB 10586 are reported. Structure-activity relationships of a variety of ester, amide and thiol ester derivatives of the nucleus, monic acid A, are described. Enhanced antimycoplasmal activity is reported for a number of monic acid A esters and the most potent derivative, m-nitrobenzyl monate A, is a 100-fold more active against Mycoplasma hyopneumoniae than pseudomonic acid A.
Asunto(s)
Antibacterianos , Antibacterianos/síntesis química , Química Farmacéutica , Ésteres/farmacología , Ácidos Grasos/farmacología , Mupirocina , Mycoplasma/efectos de los fármacos , Piranos/síntesis química , Piranos/farmacología , Relación Estructura-ActividadRESUMEN
The influence on the structure-activity relationships (S.A.R.) of the stereochemistry and various alkyl, aryl, aralkyl and heterocyclic substituents at the two chiral centres in the dipeptide side-chain of a new series of penicillins was examined. In many cases the effects of these changes had a pronounced influence on the degree of activity against Gram-positive and especially Gram-negative bacteria. Several compounds indicated that the size, shape and spatial disposition of a substituent were the parameters of importance in influencing activity, rather than it lipophilic or electronic character. The most active homologues in the series provided broad-spectrum penicillins which in terms of their in vitro antibacterial properties showed improvements over certain of the marketed penicillins. Thus 6-[D-alpha(alpha'-ureidoacyl-amino)acylamino]penicillanic acids were found which had a carbenicillin-like profile, with improvements against Pseudomonas aeruginosa, Klebsiella aerogenes, sensitive and beta-lactamase-producing Gram-positive cocci.
Asunto(s)
Penicilinas/farmacología , Bacterias/efectos de los fármacos , Biotransformación , Fenómenos Químicos , Química , Conformación Molecular , Penicilinas/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Semisynthetic analogues of pseudomonic acid A have been prepared containing a heterocyclyl substituted oxazole. Derivatives in which the heterocycle was thiophene, furan, pyridine, or isoxazole showed good antibacterial potency and were further evaluated in vivo. Both pharmacokinetic parameters and oral activity against an experimental intraperitoneal sepsis were superior to results obtained from previously described pseudomonic acid A derivatives.
Asunto(s)
Antibacterianos/química , Mupirocina/análogos & derivados , Mupirocina/química , Oxazoles/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Furanos/síntesis química , Humanos , Isoxazoles/síntesis química , Ratones , Mupirocina/uso terapéutico , Oxazoles/farmacocinética , Oxazoles/uso terapéutico , Pirazoles/síntesis química , Piridinas/síntesis química , Sepsis/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Tiazoles/síntesis química , Tiofenos/síntesis químicaRESUMEN
SB-219383 is a naturally occurring antibiotic, which acts by inhibition of tyrosyl tRNA synthetase. Semi-synthetic derivatives of SB-219383 were prepared with the objective of elucidating the key features required for inhibition of tyrosyl tRNA synthetase in order to improve the antibacterial activity. Some ester and amide derivatives as well as monocyclic analogues exhibited sub-nanomolar inhibitory activity against tyrosyl tRNA synthetase.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/enzimología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Furanos/síntesis química , Furanos/farmacología , Tirosina-ARNt Ligasa/antagonistas & inhibidores , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Furanos/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
The synthesis, antibacterial activities, murine pharmacokinetic and infection model data for a range of aryl and heteroaryl ketone derivatives of monic acid (2a) are reported. The best results were found for the 3-furyl and 2-methoxy thiazol-5-yl analogues.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Mupirocina/análogos & derivados , Mupirocina/química , Animales , Antibacterianos/farmacocinética , Humanos , Cetonas/química , Masculino , Ratones , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Mupirocina/farmacología , Sepsis/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
The in vitro activities of 12 quinolones and four antibiotics were determined against 15 veterinary mycoplasmal species and four species of bacteria commonly involved in respiratory infections in pigs. The newer quinolones were markedly more active in vitro against a wide range of mycoplasmas than nalidixic acid and the earlier quinolones. Against Mycoplasma hyopneumoniae ciprofloxacin was the most active quinolone with a geometric mean minimal inhibitory concentration (MIC) against 16 strains of 0.01 microgram ml-1 compared with 0.04 microgram ml-1 for tiamulin, 0.06 microgram ml-1 for tylosin, 0.17 microgram ml-1 for oxytetracycline and 0.23 microgram ml-1 for gentamicin. M hyosynoviae was less sensitive to the quinolones with mean MICs of 0.6 microgram ml-1 for ofloxacin and 0.7 microgram ml-1 for ciprofloxacin compared with 0.034 microgram ml-1, or less, for tiamulin. Norfloxacin and its 6-chloro analogue were both mycoplasmacidal in vitro at five or 10 times their MICs against M hyopneumoniae UCD4. Tiamulin was mycoplasmastatic. The quinolones were also active against porcine Bordetella bronchiseptica and Pasteurella multocida strains and Haemophilus species. Ciprofloxacin was the most active quinolone with mean MICs of 0.58 microgram ml-1 against B bronchiseptica (nine strains), 0.026 microgram ml-1 against P multocida (five strains) and 0.01 microgram ml-1, or less, against Haemophilus pleuropneumoniae (nine strains) and H parasuis (two strains) compared with mean MICs of from 0.5 microgram ml-1 to 64 micrograms ml-1, or more, for the antibiotics. This combination of excellent mycoplasmacidal activity against M hyopneumoniae and good antibacterial activity, suggests that the quinolones have great potential for treating respiratory infections in pigs, including enzootic pneumonia.
Asunto(s)
Antiinfecciosos/farmacología , Bordetella/efectos de los fármacos , Haemophilus/efectos de los fármacos , Mycoplasma/efectos de los fármacos , Pasteurella/efectos de los fármacos , Animales , Antibacterianos/farmacología , Diterpenos/farmacología , Gentamicinas/farmacología , Pruebas de Sensibilidad Microbiana , Norfloxacino/farmacología , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/veterinaria , Porcinos , Enfermedades de los Porcinos/microbiología , Factores de TiempoAsunto(s)
Penicilinas/farmacología , Ampicilina/farmacología , Carbenicilina/farmacología , Cloxacilina/farmacología , Escherichia coli/efectos de los fármacos , Meticilina/farmacología , Pruebas de Sensibilidad Microbiana , Penicilina G/análogos & derivados , Penicilina G/farmacología , Penicilina V/análogos & derivados , Penicilina V/farmacología , Proteus/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Salmonella typhi/efectos de los fármacos , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-Actividad , Sulbenicilina/farmacología , beta-LactamasRESUMEN
Holomycin, a member of the pyrrothine class of antibiotics, displayed broad-spectrum antibacterial activity, inhibiting a variety of gram-positive and gram-negative bacteria, with the exception of Enterobacter cloacae, Morganella morganii, and Pseudomonas aeruginosa. The antibiotic lacked activity against the eukaryotic microorganisms Saccharomyces cerevisiae and Candida kefyr. Holomycin exhibited a bacteriostatic response against Escherichia coli that was associated with rapid inhibition of RNA synthesis in whole cells. Inhibition of RNA synthesis could have been a secondary consequence of inhibiting tRNA aminoacylation, thereby inducing the stringent response. However, the levels of inhibition of RNA synthesis by holomycin were similar in a stringent and relaxed pair of E. coli strains that were isogenic except for the deletion of the relA gene. This suggests that inhibition of RNA synthesis by holomycin could reflect direct inhibition of DNA-dependent RNA polymerase. Examination of the effects of holomycin on the kinetics of the appearance of beta-galactosidase in induced E. coli cells was also consistent with inhibition of RNA polymerase at the level of RNA chain elongation. However, holomycin only weakly inhibited E. coli RNA polymerase in assays using synthetic poly(dA-dT) and plasmid templates. Furthermore, inhibition of RNA polymerase was observed only at holomycin concentrations in excess of those required to inhibit the growth of E. coli. It is possible that holomycin is a prodrug, requiring conversion in the cell to an active species that inhibits RNA polymerase.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Lactamas , Proteínas Bacterianas/biosíntesis , ADN Bacteriano/biosíntesis , ARN Polimerasas Dirigidas por ADN/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana , Nefelometría y Turbidimetría , ARN Bacteriano/biosíntesis , Rifampin/farmacología , Staphylococcus aureus/efectos de los fármacos , beta-Galactosidasa/biosíntesisRESUMEN
The biological properties of SB 205952, a nitrofuryl oxazole derivative of monic acid, differ from those of the closely related antibacterial agent mupirocin. Compared with mupirocin, SB 205952 has increased antimicrobial potency, an extended spectrum including mupirocin-resistant staphylococci, and rapid bactericidal activity. SB 205952, like mupirocin, is a potent inhibitor of bacterial isoleucyl-tRNA synthetase (IRS) in mupirocin-susceptible organisms but does not inhibit IRS from mupirocin-resistant staphylococci, indicating that SB 205952 has more than one mechanism of action. SB 205952 rapidly inhibits protein, RNA, and DNA syntheses in mupirocin-susceptible and mupirocin-resistant staphylococci. In each case, the effect on RNA synthesis is relaxed by treatment with chloramphenicol, indicating that inhibition of RNA synthesis is probably a secondary consequence of stringent control. It is proposed that SB 205952 possesses one or more mechanisms of action in addition to IRS inhibition, probably mediated by its nitrofuryl component.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Oxazoles/farmacología , Proteínas Bacterianas/biosíntesis , ADN Bacteriano/biosíntesis , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Mupirocina/farmacología , ARN Bacteriano/biosíntesis , Staphylococcus aureus/efectos de los fármacosRESUMEN
A series of beta-diketone acrylate bioisosteres 4 of pseudomonic acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents. A number of analogues have excellent antibacterial activity. Selected examples were shown to afford good blood levels and to be effective in a murine infection model.
Asunto(s)
Cetonas/síntesis química , Mupirocina/análogos & derivados , Mupirocina/síntesis química , Animales , Antibacterianos/síntesis química , Cetonas/sangre , Cetonas/farmacología , Cinética , Masculino , Ratones , Mupirocina/sangre , Mupirocina/farmacología , Staphylococcus aureus/metabolismoRESUMEN
Synthetic analogues of the microbial metabolite SB-219383 have been synthesised with defined stereochemistry. Densely functionalised hydroxylamine containing amino acids were prepared by the addition of a glycine anion equivalent to sugar-derived cyclic nitrones. One of four stereoisomeric dipeptides incorporating these novel amino acids was found to be a potent and selective inhibitor of bacterial tyrosyl tRNA synthetase, suggesting analogous stereochemistry of the natural product.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/química , Furanos/química , Furanos/síntesis química , Tirosina-ARNt Ligasa/antagonistas & inhibidores , Fenómenos Fisiológicos Bacterianos , Química Orgánica , Inhibidores Enzimáticos/síntesis química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Fenómenos Químicos Orgánicos , EstereoisomerismoRESUMEN
Aminoalkyl adenylates and aminoacyl sulfamates derived from arginine, histidine and threonine, have been prepared and tested as inhibitors of their cognate Staphylococcus aureus aminoacyl tRNA synthetases. The arginyl derivatives were both potent nanomolar inhibitors of the Class I arginyl tRNA synthetase whereas for the Class II histidyl and threonyl tRNA synthetases, the acyl sulfamates were potent inhibitors but the adenylates had very little affinity.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Aminoacil-ARNt Sintetasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Staphylococcus aureus/enzimología , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo , Adenosina Monofosfato/síntesis química , Adenosina Monofosfato/química , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacología , Inhibidores Enzimáticos/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Carbocyclic analogues of the microbial metabolite SB-219383 have been synthesised and evaluated as inhibitors of bacterial tyrosyl tRNA synthetase. One compound showed highly potent and selective nanomolar inhibition.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Furanos/química , Tirosina-ARNt Ligasa/antagonistas & inhibidores , Tirosina/análogos & derivados , Tirosina/química , Antibacterianos/química , Antibacterianos/farmacología , Bioquímica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Staphylococcus aureus/enzimologíaRESUMEN
Novel inhibitors of bacterial tyrosyl tRNA synthetase have been synthesised in which the cyclic hydroxylamine moiety of SB-219383 is replaced by C-pyranosyl derivatives. Potent and selective inhibition of bacterial tyrosyl tRNA synthetase was obtained.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inhibidores Enzimáticos/química , Furanos/química , Piranos/química , Tirosina-ARNt Ligasa/antagonistas & inhibidores , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores Enzimáticos/farmacología , Furanos/farmacología , Modelos Moleculares , Estructura Molecular , Staphylococcus aureus/enzimología , Staphylococcus aureus/metabolismoRESUMEN
Novel pyranosyl analogues of SB-219383 have been synthesised to elucidate the structure-activity relationships around the pyran ring. Analogues with highly potent stereoselective and bacterioselective inhibition of bacterial tyrosyl tRNA synthetase have been identified. A major reduction in the overall polarity of the molecule can be tolerated without loss of the nanomolar level of inhibition.