SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF CLINDAMYCIN ANALOGS - PIRLIMYCIN, A POTENT ANTIBACTERIAL AGENT

The preparation of a series of analogs of clindamycin is described in which the naturally occurring 5-membered cyclic amino acid amide portion of the molecule is replaced by a 4-, 6- or 7-membered cyclic amino acid amide. The most interesting compound was pirlimycin (U-57,930E), in which the (2S-trans)-4-n-propylhygramide portion of clindamycin was replaced by (2S-cis)-4-ethylpipecolamide. This structural modification resulted in significantly favorable changes in toxicity, metabolism and antibacterial potency. Although the in vivo antibacterial activity of clindamycin and pirlimycin was nearly identical, the latter compound was 2-20 times more active than clindamycin when administered to mice experimentally infected with strains of Staphylococcus aureus, Streptococcus pyogenes, S. pneumoniae, Bacteroides fragilis and Plasmodium berghei. Pirlimycin was absorbed in rats and mice following s.c. and oral administration. It readily penetrated B. fragilis induced abscesses in mice and was sequestered within these abscesses. A drug concentration of at least 60 times the required inhibitory concentration was maintained for 6 following a single s.c. dose of 200 mg/kg. Urinary excretion of total bioactivity consisted only of intact pirlimycin with no other antibacterially active metabolites being detected. Pirlimycin was tolerated well in rats and mice at the administered levels.