Synthesis and biological properties of N63-carboxamides of teicoplanin antibiotics. Structure-activity relationships.
The condensation of the carboxyl function of teicoplanin A2 (CTA) and its acidic hydrolysis pseudoaglycons (TB, TC) and aglycon (TD) with amines carrying various functional groups and chains produced amide derivatives with different isoelectric points and lipophilicities. Amide formation did not affect the ability of these compounds to bind to Ac2-L-Lys-D-Ala-D-Ala, a model for the natural peptide binding site in bacterial cell walls. The antimicrobial activities of teicoplanin amides were found to depend mostly on their ionic and lipophilic character and on the type and number of sugars present. Positively charged amides were generally more in vitro active than the respective unmodified antibiotics against Gram-positive organisms. In particular, most basic amides of CTA were markedly more active than teicoplanin against coagulase-negative staphylococci. A few amides of TC and most of those of TD also showed a certain activity against Gram-negative bacteria. In experimental Streptococcus pyogenes septicemia in the mouse, some basic amides were more active than the parent teicoplanins when administered subcutaneously. Some of those of CTA were also slightly more effective than teicoplanin by oral route.
Malabarba
A
A
Merrell Dow Research Institute, Lepetit Research Center, Varese, Italy.
Trani
A
A
Strazzolini
P
P
Cietto
G
G
Ferrari
P
P
Tarzia
G
G
Pallanza
R
R
Berti
M
M
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D006020:Glycopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D007525:Isoelectric Focusing; D051379:Mice; D010455:Peptides / Q000378:metabolism; D013290:Streptococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship; D017334:Teicoplanin
D000577:Amides; D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D010455:Peptides; D017334:Teicoplanin