Series Of Cephalosporins Research Articles

Orally active cephalosporins. III. Synthesis and structure-activity relationships of new 3-heterocyclicthiomethylthio-7 beta-[(Z)- 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-cephem-4 -carboxylic acids.

3-Heterocyclicthiomethylthio-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-cephem-4-carboxylic acids (2) were synthesized. Their antibacterial activity and oral absorbability were much influenced by the structure of heteroaromatic moiety in the side chain at the 3-position of a cephem nucleus. In this cephalosporin series, 3-thiadiazolylthiomethylthiocephalosporins (2k, 2l and 2m) exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria, whereas 3-(2-methyl-1,2,3-triazol-4-yl)thiomethylthiocephalosporin (2b) and 3-(pyridin-2-yl)thiomethylthiocephalosporin (2n) showed better oral absorption in mice than the other cephalosporins prepared. The structure-activity relationships of 2 are presented.

Pharmacokinetics of catechol cephalosporins. The effect of incorporating substituents into the catechol moiety on pharmacokinetics in a marmoset model.

Two series of cephalosporins A and B have been synthesized, bearing at C-3' catechols substituted with various electron withdrawing groups (Y) and differing links (X), and were evaluated for their in vitro antibacterial activity and their pharmacokinetics in marmosets. Compounds in series A, bearing an isobutyric oxime substituent, proved to be highly active against Gram-negative organisms and were especially noteworthy for showing long elimination phase (beta) half-lives in marmosets. It was established that introduction of electron withdrawing substituents greatly increased the beta half-lives of compounds (5, X = NHCO, Y = H, t1/2 = 1.25 h, AUC = 27 mg/h per L; 11, X = NHCO, Y = 5-Cl, t1/2 = 4.5 h, AUC = 638 mg/h per L) and that the nature of the link also influenced t1/2, the highest values being obtained when X = NHCO and OCO. Acidities (pKa values) of the substituted catechols were measured, and relationships between the acidities and half-lives were evaluated. Thus it was established that the more acidic catechols gave the longest half-lives (12, X = NHCO, Y = 2,5-Cl2, t1/2 = 8.2 h, AUC = 461 mg/h per L). Further elaboration of the catechol to bicyclic systems maintained good pharmacokinetics when the pKa was sufficiently acidic.

Synthesis and structure-activity relationships of a new series of cephalosporins, E1040 and related compounds.

The synthesis and in vitro antibacterial activity of a series of 7-[(Z)-2-aminoaryl-2-oxyiminoacetamido]-3-ammoniomethyl++ +-3-cephems are described. Variation of an oxyimino moiety with aminoaryl at the C-7 side chain and a quaternary ammonium moiety at the C-3 side chain were examined and structure-activity relationships were studied. E1040, the 3-(4-carbamoylquinuclidinio)methyl derivative of the 7-alpha-methoxyimino series of aminothiadiazolyl cephalosporins, exhibited excellent activity against both Gram-positive and Gram-negative bacteria, particularly against Pseudomonas aeruginosa, and possessed high stability to beta-lactamases.

Dual-action cephalosporins: cephalosporin 3'-quinolone carbamates

A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from both cephalosporin-like and quinolone-like activities, suggesting a dual mode of action. Studies to elucidate details of the mechanism of action have been inconclusive. Ciprofloxacin liberated as a consequence of bacterial enzyme-mediated reactions may contribute to the second mode of action, although some evidence indicates that the intact carbamate-linked bifunctional molecules may possess intrinsically both beta-lactam and quinolone activities.

Synthesis and antibacterial activity of new C-10 quinolonyl-cephem esters.

A series of cephalosporins derived from cephalothin containing an ester-linked quinolonyl substituent at the C-10 position (C-10 quinolonyl-cephem esters) has been prepared and evaluated for in vitro antibacterial activity. The C-10 quinolonyl-cephem esters exhibited a broadened spectrum of activity when compared with cephalothin and the corresponding quinolones, including activity against beta-lactamase-producing bacteria.

Synthesis of a new series of cephalosporins having 3-substituted-ammonio-1-propenyl group as the C-3 side chain.

The synthesis and antimicrobial activity of eight derivatives of 7-[(Z)-2-(2-aminothiazol-4-yl)- and 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido] cephalosporins having an (E) or (Z)-3-ammonio-1-propenyl group in the C-3 side chain are described. The (E)-propenyl derivatives were more active than their corresponding Z-isomers and showed well-balanced, broad antibacterial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.

ChemInform Abstract: A New Approach to the Synthesis of Aminoimidazoles: Application to the Cephalosporin Series.

AbstractThe weakly basic 7‐aminocephalosporanates (I) or (VII) are coupled with the carbodiimides (II) or (VI), yielding the guanidinium salts (III) or (IX).

A new approach to the synthesis of amino imidazoles application to the cephalosporin series

A new, mild approach to amino imidazole 10 starting from the silylated carbodiimide 9 and weakly basic amine 12 is described.

Studies on cephalosporin antibiotics. II. Synthesis, antibacterial activity and oral absorption of 3-alkoxycarbonylmethoxy-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(O-substituted oxyimino)-acetamido]cephalosporins.

The synthesis, antibacterial activity and oral absorption in rats of 3-alkoxycarbonyl-methoxy-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(O-substituted oxyimino)acetamido]cephalosporins (1) are described. In this cephalosporin series, 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxy-methoxyimino)acetamid o] cephalosporins (1b, 1i and 1j) with a lower alkoxycarbonylmethoxy group at the C-3 position of a cephem nucleus exhibited not only potent activity against Gram-negative bacteria but also good oral absorption in rats. Structure-activity relationships of 1 are also presented.

Synthesis and structure-activity relationships of a new oral cephalosporin, BMY-28100 and related compounds.

The synthesis and structure-activity relationships of 7-[D-alpha-amino-alpha-(4-hydroxyphenyl)-acetamido]-3-[(Z)-1-propenyl]- 3-cephem-4-carboxylic acid (BMY-28100) and its analogs in the 3- and 7-side chains are described. The 3-(substituted-propenyl) groups were introduced by the Wittig reaction of the 3-phosphoniomethyl cephems which were derived from the 3-chloromethyl derivatives. The reaction gave predominantly the cis isomer regarding the 3-side chain. The cis and trans isomers showed characteristic UV and 1H NMR spectra. Most of cephems of this series were well-absorbed orally and more active both in vitro and in vivo than cephalexin and cefaclor against Gram-positive organisms. Their Gram-negative activity varied depending on the 3- and 7-substituents. Compounds with a cis-propenyl group showed the best Gram-negative activity among the 3-alkenyl analogs prepared, whereas the D-4-hydroxyphenylglycyl and D-4-hydroxy-3-methoxyphenylglycyl substitutions in the 7-side chain were found suitable to improve the Gram-negative activity of 3-cis-propenyl series of cephalosporins to the level favorably compared with that of cefaclor. The 3,4-dihydroxyphenyl analog was found to be metabolized in vivo to the 4-hydroxy-3-methoxyphenyl derivative and, therefore, showed nearly the same in vivo activity as that of the latter. BMY-28100 was selected for further evaluation and the results will be reported in the subsequent paper.

Interactions of cephalosporins with the Streptomyces R61 DD-transpeptidase/carboxypeptidase. Influence of the 3'-substituent.

The influence and fate of the 3'-substituent of a series of cephalosporins on their interaction with the DD-transpeptidase/carboxypeptidase of Streptomyces R61 were investigated. Good 3'-leaving groups are eliminated from the acyl-enzyme before deacylation, and hence cephalosporins with such substituents generate a common covalent intermediate. The rate of this elimination reaction in the two cases studied in detail was much lower than from the corresponding cephalosporoates in free solution. Cephalosporins without good 3'-leaving groups yield acyl-enzymes that appear to hydrolyse, leading to enzyme re-activation, faster than those from cephalosporins with leaving groups.

Synthesis and structure-activity relationships of a new series of cephalosporins, BMY-28142 and related compounds.

The synthesis of a series of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-oxyiminoacetamido] -3-ammoniomethyl-3-cephems is described. Variations of an oxyimino moiety in the 7-side chain and a quaternary ammonium moiety in the 3-side chain were examined and structure-activity relationships studied. BMY-28142, the 3-(N-methylpyrrolidinio)methyl derivative of the 7-alpha-methoxyimino series of cephalosporins, exhibited broad antimicrobial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.

Studies on beta-lactam antibiotics. II. Synthesis and structure-activity relationships of alpha-hydroxyiminoarylacetyl cephalosporins.

The synthesis and antibacterial activity in vitro of the 2-aryl-2-hydroxyiminoacetyl cephalosporins (2) are described. Within this cephalosporin series, analogs (9f approximately 13f) with 2-hydroxyimino-2-(3-hydroxyphenyl)acetyl group at the 7-position of a cephem nucleus were found to have the highest antibacterial activity against a wide-range of microorganisms, including beta-lactamase-producing bacteria. Structure-activity relationships of 2 are discussed.

Semisynthetic cephalosporins. Synthesis and structure-activity relations of analogs with 7-acyl groups derived from 2-(cyanomethylthio)acetic acid or 2-[(2,2,2-trifluoroethyl)thio]acetic acid and their sulfoxides and sulfones

The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.

Synthesis of pivaloyloxymethyl esters of penicillins and their conversion to deacetoxycephalosporins

The chemical transformation of penicillins is an important method of obtaining compounds of the cephalosporin series, and has already found practical use in the production of cephalosporin preparations such as cephalexin and cephradin [i, 2]. The method of transformation which has received the most attention uses the trichloroethyl [I] and p-nitrobenzyl [3] esters of benzyl and phenoxymethyl penicillin sulfoxides. One of the defects of these methods is the difficulty of removing the ester-protecting groups from the carboxyl group in the final product. Hence, it was of interest to investigate the use of other peniCillin esters for the transformation, esters which would either split more readily or would give a preparation suitable for use as an ester. The acyloxymethyl esters of penicilfins [4] are compounds of this type. The possibility of using cephalosporin acyloxymethyl esters is also indicated in the literature [5].

A new parenteral cephalosporin, SK&F 59962: 7-trifluoromethylthioacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. Chemistry and structure activity relationships.

The synthesis, microbiological profile and in vivo effectiveness in laboratory animals of a series of cephalosporins having 7-acyl substituents derived from methylthioacetic acid are described. Structure-activity relationships examined include the effect of oxidation of the side-chain sulfur atom, replacement of the (side-chain) methyl hydrogens by fluorine and replacement of the 3-acetoxy substituent by thioheterocycles. One derivative, 7-trifluoromethylthioacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 59962), was found to have outstanding antibacterial activity in vitro and in vivo.

Direct displacement of the acetoxy group by halogen using boron trihalide in the cephalosporin series.

Direct displacement of the acetoxy group by halogen using boron trihalide in the cephalosporin series.