RESUMEN
Two well-known antibiotic heterocycles, the 'quinolone' nalidixic acid and the ß-lactam penicillin V, active at different levels of the bacterial growth process, have been attached via an ether-ester junction to the p-tert-butylcalix[4]arene lower rim, in alternate position. The resulting hydrophobic molecular drug-organisers were fully characterized, and evaluated over two Gram negative and three Gram positive reference strains, using disk diffusion assays with disks impregnated with solution of title compound in pure DMSO. An interesting activity was observed over Staphylococcus aureus ATCC 25923 with the dis-symmetrical podand incorporating one penicillin and one nalidixic ester moieties.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Ácido Nalidíxico/química , Ácido Nalidíxico/farmacología , Penicilina V/análogos & derivados , Penicilina V/farmacología , Antibacterianos/síntesis química , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Calixarenos/síntesis química , Calixarenos/química , Calixarenos/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Ácido Nalidíxico/síntesis química , Penicilina V/síntesis química , Staphylococcus aureus/efectos de los fármacosRESUMEN
Cycloaddition of azidoacetyl chloride to benzyl D-5,5-dimethyl-5-phenyl-2-thiazoline-4-carboxylate (1a) gave 5-phenyl-6alpha-azidopenicillanate (2a). By catalytic reduction of 2a and reaction with phenoxyacetyl chloride, 5-phenyl-6-epiphenoxymethylpenicillin benzyl ester (4a) was obtained. Oxidation of 4a gave the sulfoxide 6, which was isomerized in the presence of DBN. The sulfoxide 7 with the normal configuration could be isolated but deoxygenation of the sulfoxide was not successful. Isomerization of 4a with DBN, either with or without silylation of the side chain, gave a mixture from which 5-phenylphenoxymethylpenicillin benzyl ester (5) was isolated. Compound 5 was debenzylated to 5-phenylphenoxymethylpenicillin potassium salt (8). The antibacterial activity of 8 was low, whereas the 6-epimer 9 was inactive. Contary to published information, the 5-phenylpenam derivative 4c could be prepared by the same method.
Asunto(s)
Penicilina V/análogos & derivados , Isomerismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Penicilina V/síntesis química , Penicilina V/farmacología , Staphylococcus/efectos de los fármacos , EstereoisomerismoRESUMEN
Amino acids have been coupled to the carboxyl group of penicillin V and cephalothin by methods that keep the beta-lactam ring intact. Derivatives were successfully obtained with both neutral (Leu, Val, Ala, Ile, Trp, Tyr, Gly) and one acidic (Glu) amino acids. The new compounds were inactive in vitro against Staphylococcus aureus or Micrococcus luteus. Incubation in the presence of purified carboxypeptidases (A, B), soluble lysosomal fractions from liver, or cellular homogenates from liver, kidney, fibroblasts, and macrophages did not allow recovery of the antibacterial activity. Injection in mice also failed to cause liberation of microbiologically active compounds. HPLC studies confirmed that the amide linkage between the antibiotic and the amino acid was not hydrolyzed in the presence of soluble lysosomal fractions from liver. However, conversion of cephalothin and cephalothin-leucine to desacetyl derivatives was observed in the presence of soluble lysosomal fractions and extracts from liver and semipurified orange peel acetylesterase(s). It is concluded that amino acid derivatives of beta-lactam antibiotics do not offer potential chemotherapeutic use as prodrugs.
Asunto(s)
Carboxipeptidasas/metabolismo , Cefalotina/análogos & derivados , Lisosomas/enzimología , Penicilina V/análogos & derivados , Aminoácidos , Cefalotina/síntesis química , Cefalotina/metabolismo , Cefalotina/farmacología , Fenómenos Químicos , Química , Fibroblastos/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Pruebas de Sensibilidad Microbiana , Micrococcus/efectos de los fármacos , Penicilina V/síntesis química , Penicilina V/metabolismo , Penicilina V/farmacología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Enzymatic synthesis of phenoxymethylpenicillin from 6-aminopenicillanic acid and phenoxyacetic acid methyl ester was attempted by using partially purified alpha-acylamino-beta-lactam acylhydrolase I (ALAHase I) enzyme from Erwinia aroideae NRRL B-138. The reaction rates were carefully followed by determination of 6-aminopenicillanic acid (6-APA), phenoxymethylpenicillin (PNV), phenoxyacetic acid (POA), phenoxyacetic acid methyl ester (POM), and phenoxyacetylglycine (POG) using high performance liquid chromatography. Among the acyl donors tested, POM gave the highest yield (12.2% based on 6-APA). The overall conversion increased almost linearly with an increase in molar ratio of POM to 6-APA up to 4:1. The effects of organic solvents on the overall yield were also evaluated. Some improvement of PNV yield was observed when ethanol, 2-propanol, and acetone were used. ALAHase I was found to carry out three reactions simultaneously: transfer of acyl group to acyl acceptor to form semisynthetic beta-lactam antibiotic; hydrolysis of acyl donor in amide or ester bond, and hydrolysis of semisynthetic beta-lactam antibiotic which was produced by the enzyme. It was also observed that the hydrolysis reactions of POM and PNV were irreversible in this reaction system. The optimal pH for the three reactions was different. They were: pH 9.0 for POM hydrolysis, 6.8 for the transfer of phenoxyacetyl group to 6-APA, and 6.0 for the PNV hydrolysis. The apparent Km values for POM, 6-APA and PNV were estimated as 33, 25 and 31 mM, respectively.
Asunto(s)
Erwinia/enzimología , Penicilina V/síntesis química , HidrólisisAsunto(s)
Penicilina V/síntesis química , Bacillus subtilis/efectos de los fármacos , Remoción de Radical Alquila , Enterococcus faecalis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Métodos , Metilación , Pruebas de Sensibilidad Microbiana , Micrococcus/efectos de los fármacos , Resistencia a las Penicilinas , Penicilina V/farmacología , Penicilinasa , Sarcina/efectos de los fármacos , Staphylococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Penicillin V (S)-sulphoxide (I), treated with methanesulphonic acid in benzene and dimethylacetamide, gives the decarboxylated increment3-cephem compound (IV) and a new product of rearrangement to which the structure of the 4-[N-(1'-carboxy-2'-methylenepropyl)carbamoyl]-2-phenoxymethylthiazole (VIII) is ascribed.
Asunto(s)
Penicilina V/análogos & derivados , Espectroscopía de Resonancia Magnética , Penicilina V/síntesis química , Espectrofotometría Ultravioleta , Sulfóxidos/síntesis químicaRESUMEN
1. Phenoxymethylpenicillin sulphoxide 4-methoxybenzyl ester was labelled with 3H in its 2-beta-methyl group. Its specific radioactivity was 362 mCi/mmol. 2. Removal of the side chain of this compound yielded the corresponding ester of 6-aminopenicillanic acid sulphoxide and coupling of the latter with the appropriate protected alpha-aminoadipic acid gave 4-methoxybenzyloxycarbonylisopenicillin N sulphoxide di-4-methoxybenzyl ester or the corresponding derivative of penicillin N. 3. Removal of the protective groups by hydrogenolysis and reduction of the sulphoxide group yielded 3H-labelled isopenicillin N or penicillin N. 4. 3H-labelled phenoxymethylpenicillin sulphoxide was obtained by hydrogenolysis from its 4-methoxybenzyl ester. Reduction of its sulphoxide group and subsequent removal of the side chain gave 3H-labelled 6-aminopenicillanic acid.