Amides of de-acetylglucosaminyl-deoxy teicoplanin active against highly glycopeptide-resistant enterococci. Synthesis and antibacterial activity.
Removal, by selective reduction, of the acetylglucosamine from teicoplanin A2-2 (CTA/2) produced the 34-de(acetylglucosaminyl)-34-deoxy pseudoaglycone (II). This compound was more active in vitro than CTA/2 against coagulase-negative staphylococci (CNS). Amide derivatives obtained by condensation of the carboxyl group of II with primary amines were particularly active against Streptococcus pyogenes and had some in vitro activity against VanA enterococci highly resistant to both teicoplanin and vancomycin. Among them, a carboxamide (VII) with a branched tetramine also had better activity than the corresponding amide of teicoplanin against CNS. In contrast, the dimethylamide (VIII) of II had little activity against VanA enterococci. While the overall structure of the heptapeptide backbone of the secondary carboxamides of II is the same as in CTA/2 and its amide derivatives, in deoxy pseudoaglycone II and its tertiary amide VIII the 51,52-peptide bond undergoes a conformational change from the original cisoid to the transoid orientation. This difference between the secondary amides of II and dimethylamide VIII is reflected in their different antibacterial spectrum. The direct synthesis of the amides of deoxy pseudoaglycone II from parent CTA/2-amides by reaction with sodium borohydride is also described.
Malabarba
A
A
Marion Merrell Dow Research Institute, Lepetit Center, Gerenzano (Varese), Italy.
Ciabatti
R
R
Kettenring
J
J
Ferrari
P
P
Scotti
R
R
Goldstein
B P
BP
Denaro
M
M
D000577:Amides / Q000737:chemistry; D004352:Drug Resistance, Microbial; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013297:Streptococcus pyogenes / Q000187:drug effects*; D017334:Teicoplanin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000577:Amides; D017334:Teicoplanin