Synthesis and antibacterial evaluation of N-alkyl vancomycins.

Abstract

Over eighty iV-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The 7V-alkyl vancomycins exhibit greater antibacterial activity than the corresponding iV-acyl vancomycins and the parent antibiotic.Some of these semisynthetic vancomycins are five times more active than vancomycin. The AT-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.For the past 30 years, vancomycin has been the drug of choice to treat severe Gram-positive infections caused by methicillin-resistant Staphylococcus aureus. Recent reports have described glycopeptides with acylamido side chains on a sugar residue,2~6) and some of these compounds, e.g. teicoplanin, have been claimed to have more favorable antibacterial and pharmacokinetic properties than vancomycin.70 Synthesis of several iV-acyl vancomycins and structure activity relationship studies revealed no substantial advantage of these iV-acyl vancomycins over the parent antibiotic.8) As an extension to the structure-activity relationship (SAR) of the iV-acyl vancomycin research, we undertook the synthesis and evaluation of iV-alkyl vancomycins. ChemistryThe AT-alkyl vancomycins were obtained by reductive alkylation of vancomycin with the appropriate aldehydes. This reaction could yield two mono-7V-alkyl derivatives substituted at the amino groups of vancosamine sugar and iV-methyl leucine residue, respectively, and one di-N-alkyl vancomycin. The reaction products were monitored by analytical HPLC. Not all reactions produced all the three possible products. However, if all three iV-alkyl vancomycins were available in a series, the retention times of the iV-alkyl vancomycins were diagnostic of the site of alkylation as previously observed for the iV-acyl derivatives.50 The mono-iV-alkyl derivative substituted on vancosamine eluted first, then the second mono-iV-alkyl vancomycin functionalized on JV-methyl leucine, and finally the di-iV-alkyl vancomycin (see Table 1).The ratio of the three 7V-alkyl vancomycins from the reductive alkylation reaction depended on the reaction conditions which could be adjusted to yield the desired iV-alkyl derivative as the major product. The reaction mixture was purified by preparative HPLC.The structures of the iV-alkyl vancomycins were confirmed by fast atom bombardment mass spectrometry (FAB-MS). The molecular ion indicates if the derivatives is a mono-or di-iV-alkyl vancomycin. The fragmentation pattern of the mono-7V-alkyl derivative clearly establishes the site of substitution between the two alternative amino groups in vancomycin. Thus, the mono-iV-alkyl vancomycin alkylated on the JV-methyl leucine affords the disaccharide, vancosaminyl-O-glucose and vanf Seerefl.

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by 13C{19F} and 15N{19F} Rotational-Echo Double Resonance

“…FPBV was synthesized by reaction of the vancosamine sugar amine with 4-fluorophenyl-benzaldehyde, as described by Nagarajan, et. al (17). Briefly, to fifty mg (33 μmol) of vancomycin dissolved in 1 ml of water were added 12 ml of 50:50 V:V MeOH:DMF and 3 mg of 4-fluorobenzaldehyde (24 μmol).…”

Lipopeptides as anti-infectives: a practical perspective

“…Unfortunately, this hydrophobic group imparts unfavourable absorption, distribution, metabolism and excretion (ADME) profiles, resulting in a long elimination half-life and high tissue accumulation along with poor excretion and distribution to liver and kidney tissue [100,101]. In terms of activity, the lipid tail confers membrane perturbing properties in bacteria at higher concentrations [102].…”

Antibacterial activities and modes of action of vancomycin and related glycopeptides

“…As an extension to the above-described SAR of N-acyl vancomycins, over 80 N-alkyl vancomycins were synthesized and evaluated (28). A comparison of the antibacterial activities of the N-decyl vancomycins and the corresponding N-decanoyl vancomycins shows that the C1o alkyl analogs are more active than the corresponding alkanoyl series.…”