Synthesis and antimicrobial activity of clindamycin analogues: pirlimycin, 1,2 a potent antibacterial agent.
The preparation of a series of analogues of clindamycin is described in which the naturally occurring five-membered cyclic amino acid amide portion of the molecule is replaced by a four-, six-, or seven-membered cyclic amino acid amide. The most interesting compound is pirlimycin (7e, U-57,930E), in which the (2S-trans)-4-n-propylhygramide portion of clindamycin is replaced by (2S-cis)-4-ethylpipecolamide. This structural modification results in significantly favorable changes in toxicity, metabolism, and antibacterial potency. Although the in vitro antibacterial activity of clindamycin and pirlimycin are nearly identical, the latter compound is 2-20 times more active than clindamycin when administered to mice experimentally infected with strains of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Bacteroides fragilis, and Plasmodium berghei. Pirlimycin is absorbed in rats and mice following both subcutaneous and oral administration. It readily penetrates B. fragilis induced abscesses in mice and is sequestered within these abscesses. A drug concentration of at least 60 times the required inhibitory concentration is maintained for 6 h following a single subcutaneous dose of 200 mg/kg. Urinary excretion of total bioactivity consists only of intact pirlimycin with no other antibacterially active metabolites being detected. Pirlimycin is tolerated well in rats and mice at the administered levels.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001442:Bacteroides Infections / Q000188:drug therapy; D001441:Bacteroides fragilis; D002981:Clindamycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei; D013203:Staphylococcal Infections / Q000188:drug therapy; D013290:Streptococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002981:Clindamycin; C034093:pirlimycin