Synthesis and antimicrobial activity of chloramphenicol–polyamine conjugates

• Published in: Bioorganic & medicinal chemistry 2015-07, Vol.23 (13), p.3163-3174
• Main Authors: Magoulas, George E., Kostopoulou, Ourania N., Garnelis, Thomas, Athanassopoulos, Constantinos M., Kournoutou, Georgia G., Leotsinidis, Michael, Dinos, George P., Papaioannou, Dionissios, Kalpaxis, Dimitrios L.
• Format: Article
• Language: English
• Subjects: Acetyltransferases - antagonists & inhibitors; Acetyltransferases - genetics; Acetyltransferases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Chloramphenicol; Chloramphenicol - chemistry; Enzyme Assays; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - growth & development; Escherichia coli - metabolism; Gene Expression; Kinetics; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Methicillin-Resistant Staphylococcus aureus - growth & development; Methicillin-Resistant Staphylococcus aureus - metabolism; Microbial Sensitivity Tests; Mutation; Phthalic Anhydrides - chemistry; Polyamine conjugates; Polyamine uptake system; Polyamines; Spermidine - chemistry; Succinic Anhydrides - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.04.069

[Display omitted] A series of chloramphenicol (CAM) amides with polyamines (PAs), suitable for structure–activity relationship studies, were synthesized either by direct attachment of the PA chain on the 2-aminopropane-1,3-diol backbone of CAM, previously oxidized selectively at its primary hydroxyl group, or from chloramphenicol base (CLB) through acylation with succinic or phthalic anhydride and finally coupling with a PA. Conjugates 4 and 5, in which the CLB moiety was attached on N4 and N1 positions, respectively, of the N8,N8-dibenzylated spermidine through the succinate linker, were the most potent antibacterial agents. Both conjugates were internalized into Escherichia coli cells by using the spermidine-preferential uptake system and caused decrease in protein and polyamine content of the cells. Noteworthy, conjugate 4 displayed comparable activity to CAM in MRSA or wild-type strains of Staphylococcus aureus and Escherichia coli, but superior activity in E. coli strains possessing ribosomal mutations or expressing the CAM acetyltransferase (cat) gene. Lead compounds, and in particular conjugate 4, have been therefore discovered during the course of the present work with clinical potential.