Synthesis and structure-activity relationships of some 6 beta-acrylamido penicillins.

Syntheses are described for penicillins (4b approximately 4i, 5a and 5b) which possess a 6 beta-(2-heteroaryl-3-substituted)-propenamido side-chain of fixed geometry. In vitro results for these compounds against a range of Gram-positive and Gram-negative bacteria showed in most cases good stability against both penicillinase and TEM-1 beta-lactamase; analogues (4b approximately 4i) bearing a 2-(2-aminothiazol-4-yl) unit showed the best intrinsic activity, the cyclohexyl compound (4b) being the most promising. The 1-acetoxyethyl ester (6) of 4b was also prepared; in experimental animal studies the in vivo properties of this compound compared favourably with cefuroxime axetil and are reported together with selected in vivo data for the other compounds.

BRL 20330, an oral prodrug of temocillin: bioavailability studies in man.

BRL 20330 is the o-methyl phenyl ester of temocillin which is well absorbed after oral administration and converted to temocillin in the body. BRL 20330 was administered to healthy subjects in a three-part cross-over study with single doses equivalent to 400, 600 and 800 mg of temocillin. Peak serum concentrations of temocillin were 9.8, 12.8 and 15.8 mg/l respectively and concentrations of 3.0-6.0 mg/l were measured at 12 h after dosing. High and prolonged concentrations of temocillin were measured in the urine. The mean urinary recovery was 22-25% and only 0.2% of unhydrolyzed BRL 20330 was detected in the urine. Little difference in the extent of absorption was noted when BRL 20330 was administered with food although the peak levels of temocillin were delayed and reduced slightly. Urinary concentrations of temocillin, even after 24 h, were bactericidal for a number of Gram-negative bacteria including multi-resistant strains. BRL 20330 was well tolerated and there was no evidence of gastro-intestinal adverse effects.

In vitro antibacterial properties of BRL 36650, a novel 6 alpha-substituted penicillin.

BRL 36650 is a new type of penicillin in which a formamido group has been introduced into the 6 alpha-position of the nucleus. The compound is highly active against aerobic gram-negative bacteria and is stable to a wide range of beta-lactamases produced by these organisms. Against members of the family Enterobacteriaceae, BRL 36650 was considerably more active than piperacillin, particularly against beta-lactamase-producing strains, and showed a similar level of activity to moxalactam, aztreonam, and the third-generation cephalosporins cefotaxime and ceftazidime. Against Pseudomonas aeruginosa and other Pseudomonas species, BRL 36650 was more active than piperacillin, cefoperazone, and aztreonam and compared favorably with ceftazidime. BRL 36650 was highly active against Haemophilus influenzae and Neisseria gonorrhoeae, including beta-lactamase-producing strains, and against Acinetobacter calcoaceticus. Clinical isolates of Enterobacter species and P. aeruginosa which showed markedly reduced susceptibility to cefotaxime, ceftazidime, and aztreonam were only slightly less susceptible to BRL 36650. Against Bacteroides fragilis and most gram-positive bacteria, BRL 36650 showed only a low level of activity. BRL 36650 was found to be only 35% bound to human serum protein, and the antibacterial activity was little affected by the presence of serum. In contrast, the composition of the test medium influenced the activity of BRL 36650 slightly, and an antagonistic effect could be demonstrated between the compound and a component of certain Mueller-Hinton media.

Comparative biological properties of some synthetic olivanic acid analogues.

A series of olivanic acid/thienamycin analogues have been prepared by total synthesis. Particular attention was given to the effect of the side-chain substituents on the chemical, beta-lactamase and metabolic stability of the final products. All of the compounds possessed a broad and high level of in vitro antibacterial activity against Gram-positive and Gram-negative organisms including beta-lactamase-producing strains. Two derivatives (8c) and (8j) were selected for further evaluation on the basis of in vitro activity, ease of synthesis and stability parameters. The improved metabolic stability of the selected analogues, relative to the naturally-occurring olivanic acid, MM 13902, could be demonstrated in terms of better activity, higher blood levels and improved urinary recovery in in vivo studies in mice.

Antibacterial halogenoacetyl derivatives of amino acids and simple peptides.

The vital role of D-alanine and L-lysine in the peptidoglycan crosslinking process in the bacterial cell wall prompted preparation of various small peptides incorporating these amino acids. N-Iodoacetyl or -bromoacetyl derivatives of the peptides were then prepared in the hope that they would serve as active-site-directed irreversible inhibitors of cell wall transpeptidases. Certain of the halogenoacetyl dipeptide esters, but not the corresponding free acids, showed slight antistaphylococcal activity. Subsequent structural variation showed that inclusion of C-alanine or L-lysine was not necessary, since antibacterial activity was at least as good when the dipeptide unite was replaced by glycylglycine or by an omega-aminoalkanoic acid. It was concluded that the observed antibacterial activity was probably not due to specific inhibition of a cell wall transpeptidase.