Synthesis and antimicrobial activity of clindamycin analogs: pirlimycin, a potent antibacterial agent

Abstract

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.

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT2C Receptor Allosteric Modulators

“…Given the similarity in the chemical structures of PNU-69176E and pirlimycin, and because our synthetic approach followed that of the literature, 6 we assigned the stereochemistry of these two products analogously to that of pirlimycin and its diastereomer; these assignments were confirmed by X-ray analysis. 6 The configuration of the more polar isomer was assigned as cis-2S,4R and named PNU-69176E (1), while the less polar product was assigned as cis-2R,4S, the diastereomer 2 of PNU-69176E. The lipophilicity of undecyl long alkyl chain is problematic to the growth of single crystals from either PNU-69176E or its diastereomer to unambiguously confirm their configurations.…”

“…8 Following a procedure similar to that reported by Birkenmeyer et al, 6 the picolinic acid derivative 6 was reacted with isobutyl chloroformate to give a mixed anhydride, which was further coupled with 7-Cl-MTL (9) to afford 4-(undec-1-ynyl)-2-pyridinecarboxamide (10) in 39% yield.…”

“…− 4-Undec-1-ynyl-pyridine-2-carboxylic Acid (6). Lithium hydroxide monohydrate (313 mg, 13.6 mmol, 1.5 equiv) was added to a solution of 5 (2.5 g, 8.7 mmol, 1 equiv) in tetrahydrofuran (THF; 12 mL) and H 2 O (3 mL).…”

Activity of pirlimycin against pathogens from cows with mastitis and recommendations for disk diffusion tests

“…This is the same concentration that was selected for clindamycin, of which pirlimycin is an analog, but that was not a major selection criterion (2).…”

“…The exceptions are the rare antimicrobial agents for which significant levels of drug accumulate in the urine but not in blood or tissue. In the therapy of bovine mastitis, the drugs are infused directly into the udder, making concentrations in milk the major param and it has potent activity against many gram-positive cocci, including staphylococci and streptococci (2,13). The use of pirlimycin would be facilitated if antimicrobial susceptibility tests could be performed on the isolates from mastitis specimens with breakpoints developed specifically for mastitis therapy.…”