Structure-activity relationships within a series of C(7)-substitutedoxyiminocephalosporins containing the C(3)-methylaminopyridiniumthiomethyl substituent. Synthesis and biological properties of BRL 57342 and some close analogues.

(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-[(Z)-[(S)-carboxy(3,4- dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(1-methylaminopyri dinium-4-thiomethyl)ceph-3-em-4-carboxylate sodium salt (BRL 57342, 1f) combines excellent in vitro antibacterial potency against Gram-positive and Gram-negative bacteria, including P. aeruginosa and Acinetobacter spp., with excellent stability to extended spectrum beta-lactamases. This potency is reflected in in vivo efficacy studies.

Synthesis and biological activity of 3-(N-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins.

The synthesis and antibacterial activity of a series of 3-(1-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins is described. All the derivatives showed good potency and stability to bacterial beta-lactamases. The antibacterial efficacy seen with the N-alkyl pyridinium substituents was enhanced by the introduction of a catecholic side chain at C-7 and by preparation of N-(substituted amino)pyridinium derivatives.

Synthesis and biological properties of some 3-[(N-substituted-amino)pyridinium-4-thiomethyl]-7-[2-(2-amino-thiazol- 4-yl)-2-(Z)-(methoxyimino)acetamido]ceph-3-em-4-carboxylates.

The synthesis and antibacterial activity of a series of beta-lactamase stable, broad spectrum 7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-cephalo sporins, characterised by a C-3-[N-(substituted-amino)pyridinium-4-thiomethyl] group, is described. Gram-positive and Gram-negative bacteria including extended spectrum beta-lactamase-producing strains were most susceptible to the N-amino- and N-methylamino derivatives (3a) and (3b); with the exception of Pseudomonas aeruginosa, (3b) was more active in vitro and in vivo than cefpirome or ceftazidime.

Structure-activity relationships in a series of piperazine-2,3-dione containing penicillins and cephalosporins. II. Derivatives substituted at N(4) of the piperazine ring.

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.

Synthesis and biological activity of a series of piperazine-2,3-dione containing penicillins and 6 alpha-formamidopenicillins. I. Derivatives substituted at C(5) or C(6) of the piperazine ring.

The synthesis and antibacterial activity of a series of penicillins and 6 alpha-formamidopenicillins containing a C(5) or C(6)-substituted piperazine-2,3-dione moiety in the C(6)-beta-sidechain is described.

Studies on semi-synthetic 7 alpha-formamidocephalosporins. III. Synthesis and antibacterial activity of some 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl amino] acetamido]-7 alpha-formamidoceph-3-em-4-carboxylate derivatives.

The synthesis and antibacterial activity of 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl) carbonylamino] acetamido]-7 alpha-formamidocephalosporins with various substituents at the C-3 position of the cephalosporin nucleus is described. Inhibition of Gram-positive and Gram-negative bacteria including beta-lactamase producing strains was observed with phenyl as the aryl residue. The 3,4-dihydroxyphenyl group further enhanced the activity against Gram-negative organisms; in this series, the 3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] and 3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl] analogues (2 and 12b) exhibited exceptional activity against Gram-negative bacteria, including Pseudomonas aeruginosa.

Preparation and structure-activity relationships of some 6 alpha-substituted penicillins.

The influence on the antibacterial activity of introducing a 6 alpha-methoxy group into carbenicillin, and various 6 alpha-substituents into sulbenicillin and piperacillin was examined. Further variations of the side chain aryl group were examined in the 6 alpha-methoxy substituted series. This led to the identification of disodium 6 beta-(D,L-2-carboxy-2-thien-3-ylacetamido)-6 alpha-methoxypenicillanate (5b) as a beta-lactamase stable derivative with useful activity against Enterobacteriaceae, and disodium 6 beta-[D-2-(4-aminophenyl)-2-sulfoacetamido]-6 alpha-methoxypenicillanate (6e) with slightly lower activity against the Enterobacteriaceae but more active against Pseudomonas aeruginosa.

beta-lactam antibiotics. II. Structure-activity relationships of 6-[alpha-(alpha'-ureido-acylamino) acylamino] penicillanic acids.

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.