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1.
The synthesis and antibacterial activity of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(hydroxy or alkoxy)iminoacetamido]cephalosporins with various thiadiazolylthiomethyl moieties at the 3-position are discussed. Of the compounds (1a-1e, 7a-7d), 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(1,2 ,4- thiadiazol-5-yl)thiomethyl]cephalosporin (1d: FK312) exhibited the highest activity against Gram-positive and Gram-negative bacteria, especially, against methicillin-resistant Staphylococcus aureus. Furthermore, the pharmacokinetic profiles of the compound 1d showed longer serum levels than that of ceftriaxone in rats. 相似文献
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D B Boyd 《Journal of medicinal chemistry》1979,22(5):533-537
The three-dimensional structures of various penicillins and cephalosporins are compared to the spatial characteristics of glycylglycine and the tetrahedral adducts formed when a nucleophile attaches to the amide carbonyl carbon of this dipeptide. The dipeptide is taken to model the D-alanyl-D-alanine terminus of the precursors of bacterial cell-wall peptidoglycan cross-links. Least-squares fitting shows that the spatial match between the dipeptide and the antibiotic depends on the thiazolidine or dihydrothiazine ring conformation, as well as the conformation of the dipeptide. In general, the tetrahedral adducts fit somewhat better than the parent dipeptide. A previously unobserved 3-cephem conformer is found by molecular mechanics calculations to be less stable than the usual crystallographically observed conformer. 相似文献
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1 The saturability of the tubular excretion of cloxacillin, benzylpenicillin and cephradine was investigated. 2 Volunteers received a continuous infusion of one of the antibiotics at increasing infusion rates in order to maintain constant plasma concentrations at three different levels. Blood and urine samples were taken every 30 min. Sufficient urinary flow was ensured by a saline infusion (500 ml h-1). 3 Renal clearance of the antibiotic was calculated for the non-protein bound fraction of the drug. 4 Tubular clearance and tubular excretion rate were estimated by using the renal clearance of the antibiotic minus the glomerular filtration rate; the latter was considered to be equal to creatinine clearance. 5 Data were fitted to a Scatchard transformation and, by nonlinear methods, to a Michaelis-Menten equation. 6 Parameters of saturability, i.e. EC50 and maximal tubular excretion rate, were established. The values found for EC50 were 7.7, 93.0 and 266 mg l-1 for cloxacillin, benzylpenicillin and cephradine, respectively. The values calculated for the maximal tubular excretion rate were 1017, 5535 and 4537 mg h-1, respectively. 相似文献
4.
Two penicillins and 5 cephalosporins were evaluated for their ability to pass through the outer-membranes of Proteus morganii, Citrobacter freundii and Escherichia coli. Cefazolin, ceftezole and cephaloridine showed high permeability through the outer-membranes of these Gram-negative bacteria. Benzylpenicillin and cephalothin, on the contrary, showed low permeability. The outer-membrane permeability of ampicillin and cephalexin varied from species to species. C. freundii was found to have the highest barrier against both the penicillins and the cephalosporins, and E. coli appeared to have a low barrier against the cephalosporins. The hydrophobic character of the beta-lactam antibiotics, which was estimated by a reversed-phase thin-layer chromatography was closely related to the outer-membrane permeability. In general, the more hydrophilic antibiotic showed the higher outer-membrane permeability. However, cephaloridine, the most lipophilic compound among the antibiotics tested, showed good permeability. 相似文献
5.
Representatives of three types of side-chain analogues of distamycin A (1) were synthesized. These were tested for cytotoxicity, inhibition of herpes simplex virus (HSV) replication in cultured cells, effects on the synthesis of HSV DNA in isolated nuclei in vitro, as well as on DNA synthesis by purified HSV DNA polymerase. Distamycin A was the most active compound in all three antiviral tests, as well as the most toxic. However, several compounds, in particular the aromatic analogues 15 and 16, showed no toxicity under the experimental conditions used but were still very active in the three antiviral tests. 相似文献
6.
Synthesis and in vitro antibacterial activity of semisynthetic cephalosporins (I) having an alpha-substituted 2-(2-amino-4-thiazolyl)acetyl side chain at the 7-position were described. 相似文献
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Stereoselective uptake of beta-lactam antibiotics by the intestinal peptide transporter. 总被引:2,自引:0,他引:2
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1. The stereoselective transport of beta-lactam antibiotics has been investigated in the human intestinal epithelial cell line, Caco-2, by use of D- and L-enantiomers of cephalexin and loracarbef as substrates. 2. The L-isomers of cephalexin, loracarbef and dipeptides displayed a higher affinity for the oligopeptide/H(+)-symporter in Caco-2 cells than the D-isomers. This was demonstrated by inhibition of the influx of the beta-lactam, [3H]-cefadroxil. 3. By measurement of the substrate-induced intracellular acidification in Caco-2 cells loaded with the pH-sensitive fluorescent dye BCECF (2',7'-bis(2-carboxyethyl)-5-(6)-carboxy-fluorescein), it was demonstrated for the first time that L-isomers of beta-lactams not only bind to the peptide transporter with high affinity but are indeed transported. 4. Efficient proton-coupled transport of L-beta-lactam antibiotics was also shown to occur in Xenopus laevis oocytes expressing the cloned peptide transporter PepT1 from rabbit small intestine. 5. Both cell systems therefore express a stereoselective transport pathway for beta-lactam antibiotics with very similar characteristics and may prove useful for screening rapidly the oral availability of peptide-derived drugs. 相似文献
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Phospholipid bilayer permeability of beta-lactam antibiotics 总被引:2,自引:0,他引:2
Liposomes containing penicillinase or cephalosporinase were prepared from the phospholipids of Escherichia coli. After free beta-lactamase was inactivated by clavulanic acid or penicillanic acid sulfone followed by separation of inactivated enzyme and inhibitor from liposomes by gel filtration, the permeability of these liposomes to ampicillin, cefazolin and cephaloridine was estimated by measuring the hydrolysis of these antibiotics by the entrapped enzymes. The permeability parameter C (minute-1 microM lipid-1) of ampicillin, cefazolin and cephaloridine was calculated to be 2.35 X 10(-4), 0.33 X 10(-4) and 0.52 X 10(-4), respectively. The lipid bilayer permeability of these antibiotics was also measured by using the liposomes containing these antibiotics. About half of the initially entrapped ampicillin was released from the liposomes within 80 minutes, while no significant release of cefazolin and cephaloridine could be detected during the same period. These results clearly indicates that the lipid bilayer membrane is more permeable to ampicillin than cefazolin and cephaloridine, and they are consistent with the observations of Sawai et al., who showed that ampicillin was a more effective antibacterial drug than cefazolin and cephaloridine against the porin-deficient mutants. 相似文献
13.
T Matsubara S Otsubo A Ogawa J Okamoto T Yoshizaki Y Nishibe Y Tochino E Hirai 《Japanese journal of pharmacology》1986,42(3):333-343
Several beta-lactam antibiotics, especially those containing N-methyltetrazolylthiomethyl groups at the 3-position of the cephalosporin nucleus, affect the alcohol-metabolizing system in rats. These effects were compared those with disulfiram, well-known as a potent inhibitor of aldehyde dehydrogenase (ALDH). Both disulfiram and antibiotics containing the N-methyltetrazolylthiomethyl group inhibited both mitochondrial low Km ALDH and acetaldehyde oxidation in rat livers. The high Km ALDH and alcohol dehydrogenase activities in livers were not affected by these treatments. When ethanol was given to rats pretreated with disulfiram or these antibiotics, the blood acetaldehyde concentration increased markedly concomitant with a decrease in activity of the low Km ALDH. Administration of N-methyltetrazolethiol alone suppressed the low Km enzyme activity and also increased the blood acetaldehyde level; both effects were pronounced and observed several hours after administration. beta-Lactam antibiotics without N-methyltetrazolethiol in their molecule did not affect the liver mitochondrial enzyme activity or the blood acetaldehyde level. 相似文献
14.
Gastrointestinal absorption of cefazolin, which is poorly absorbed in adults, and of cephradine, which is well absorbed in adults, was studied in rats during their development. Significantly higher concentrations of cefazolin in plasma after oral administration were observed in 1- and 2-week-old rats compared with 3-week-old and adult rats. A marked difference in the absorption of cefazolin by 2- and 3-week-old rats (at weaning period) was observed. No such marked difference in the absorption of cephradine by rats of various age groups was found. With cefazolin, a similar pattern of developmental change in jejunal uptake was observed. Cortisone, which causes early maturation of the intestinal membrane, was given as a preweaning injection to 2-week-old rats. This treatment decreased concentrations of cefazolin in plasma and jejunal uptake of cefazolin. Thus, the absorption of cefazolin in 1- and 2-week-old rats seems to depend on the permeability of the immature intestinal membrane before weaning. Cephradine absorption from the intestine of 1-week-old rats became saturated and inhibited by carnosine and glycylglycine when studied by the in situ loop method. Cefazolin absorption was proportional to luminally administered doses and was not affected by carnosine and glycylglycine. A nonsaturable process for cefazolin and a saturable process for cephradine were also observed in an in vitro uptake experiment. 相似文献
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ZBIGNIEW SZEWCZUK ALEKSANDRA KUBIK IGNACY Z. SIEMION ZBIGNIEW WIECZOREK KRYSTYNA SPIEGEL MICHAL ZIMECKI MARIA JANUSZ J
ZEF LISOWSKI 《Chemical biology & drug design》1988,32(2):98-103
PRP-hexapeptide possessing the azo-bridge between Tyr1 and Phe5 residues, called azo-PRP-hexapeptide: Tyr-Val-Pro-Leu-Phe-Pro, was synthesized and tested for immunoregulatory activity. High biological activity of the synthesized azo-PRP-hexapeptide suggests that the biologically active conformation of PRP-hexapeptide must be such that both aromatic rings (Tyr and Phe) are apparently close to each other. 相似文献
16.
A study was done on the combined actions of an aminoglycoside, isepamicin (ISP), and 3 beta-lactam antibiotics (cefoperazone (CPZ), latamoxef (LMOX) and imipenem/cilastatin sodium (IPM/CS] against clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Minimal inhibitory concentrations of individual antibiotics were compared first. ISP and IPM/CS had strong antibacterial activities against all 3 bacterial species while the antibacterial activities of CPZ against P. aeruginosa and S. marcescens, and that of LMOX against P. aeruginosa were much weaker than those of IPM/CS or ISP. Fractional inhibitory concentration indices determined by the checker-board dilution method were compared next. ISP, when used in combination with beta-lactam antibiotics (CPZ, LMOX, or IPM/CS), showed synergistic or additive effect on most strains of the all 3 species, the combination of ISP and CPZ being most effective. Although less effective, synergistic or additive effects were also observed with the combinations of 2 beta-lactam antibiotics (CPZ and IPM/CS, LMOX and IPM/CS). Time course experiments demonstrated that ISP combined with CPZ had bactericidal activities against all 3 bacterial species at concentrations at which the respective drug alone showed only bacteriostatic activity. 相似文献
17.
R Monguzzi M Pinza G Pifferi M Visconti G Broccali 《Il Farmaco; edizione scientifica》1985,40(12):956-969
Using as a model cephalosporins with an alpha-hydroxyimino moiety in the side chain, some new (E)-alpha-hydrazono and alpha-methylhydrazono benzyl cephalosporins were prepared. While the synthesis of methylhydrazono-derivatives (I a-d) involved direct condensation of the methylhydrazionacid (II a-b) with a protected 7-aminocephalosporanic derivative, the N-unsubstituted compounds (I e-f) had to be prepared from the N-acyl protected hydrazono acids (III a-d). The cephalosporin (I f) was also obtained as Z-isomer by condensation of the corresponding alpha-oxo compound with 4-nitrobenzyloxycarbonylhydrazine, chromatographic separation of the obtained E-Z mixture, and hydrogenolysis of the Z form. The in vitro antibacterial evaluation showed that N-methyl substitution is favorable among the E compounds, whereas among the N-unsubstituted hydrazono derivatives, the compound Z-(I f), although less stable, is much more potent than the corresponding E-isomer. 相似文献
18.
Two simple and selective spectrophotometric methods were developed for the quantitative determination of cefoperazone sodium, cefadroxil monohydrate, cefprozil anhydrous and amoxicillin trihydrate in pure forms as well as in their pharmaceutical formulations. The methods are based on the selective oxidation of these drugs with either Ce (IV) or Fe (III) in acid medium to give an intense yellow coloured product (lambda(max)=397 nm). The reaction conditions were studied and optimized. Beer's plots were obeyed in a general concentration range of 5-30 microg ml(-1) with correlation coefficients not less than 0.9979 for the four drugs with the two reagents. The methods are successfully applied to the analysis of pharmaceutical formulations containing amoxicillin, either alone or in combination with potassium clavulanate, flucloxacillin or dicloxacillin. They were also applied to the analysis of the other three studied drugs in vials, capsules, tablets and suspensions with good recovery; percent ranged from 99.7 (+/-0.46) to 100.32 (+/-1.05) in the Ce (IV) method and 99.6 (+/-0.50) to 100.3 (+/-1.32) in the Fe (III) method. Interferences from other antibiotics and additives products were investigated. 相似文献
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