Synthesis and antibacterial activity of a series of basic amides of teicoplanin and deglucoteicoplanin with polyamines

Abstract

Basic carboxamides of teicoplanin A2 (CTA) and its aglycon (TD) are prepared by condensation of the 63-carboxyl function of these antibiotics with linear or branched polyamines. The antimicrobial activities of some of the resulting compounds were better than those of the unmodified antibiotics. The presence of more than one basic group in the amidic chain enhanced the in vitro activity of some TD-amides against Gram-negative bacteria; two of these derivatives were also effective in vivo against Escherichia coli septicemia in the mouse. Among the CTA derivatives, the amide with spermine showed some unexpected in vitro activity against Gram-negatives. Both CTA- and TD-amides with polyamines are very soluble in water over a wide range of pH and are very hydrophilic.

Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics

“…[317] Furthermore, the teicoplanin aglycon-derived poly-(aminopropyl)amides 324 and 325 (Scheme 84) also exhibited significant antibiotic activity against Gram-negative bacteria. [318] In their mode of action, these modified glycopeptides do not differ from their parent compounds except for their ability to traverse the outer membrane of the Gram-negative bacteria by a self-promoted uptake mechanism. [319] Considerable efforts have been expended in modifying the cyclopeptide core of the glycopeptide antibiotics.…”

Structural modifications of glycopeptide antibiotics

“…Amides of CTA, TB, TC, and TD. 29,62 Methyl (T-MeA) or ethyl amides of teicoplanin antibiotics were prepared by preliminary activation of the carboxy group of N 15 -CBZ derivatives (N-CBZ-T) as cyanomethyl ester (CME), followed by reaction with methanolic methyl or dimethylamine, and final deprotection of the N-terminus by catalytic hydrogenation (Scheme 10). In terms of in vitro activity, no significant improvement over corresponding T-MeE or HM-T compounds was observed with the T-MeA derivatives, except for better antistaphylococcal activity of the CTA derivative.…”

Mechanism of uptake of deglucoteicoplanin amide derivatives across outer membranes of Escherichia coli and Pseudomonas aeruginosa

“…The parent compound of the deglucoteicoplanin amides (R = NH2 in Fig. 1) had an MIC of 16 ,ug/ml for E. coli but an unmeasurable MIC for P. aeruginosa (Table 1) (9). In contrast, 766 had MICs of 2 ,ug/ml for E. coli and 8 ,ug/ml for P. aeruginosa, whereas 934 was two-to fourfold less effective for both species ( (11).…”