β-LACTAM ANTIBIOTICS. II: STRUCTURE-ACTIVITY RELATIONSHIPS OF 6-[α-(α'-UREIDOACYLAMINO) 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 its 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-α(α'-ureidoacylamino) acylamino]penicillanic acids were found which had a carbenicillin-like profile, with improvements against Pseudonionas aeruginosa, Klebsiella aerogenes, sensitive and β-lactamaseproducing Gram-positive cocci.