title: Synthesis and antimicrobial activity of chloramphenicol-polyamine conjugates.
abstract: 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 N(8),N(8)-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.
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece.
authors.forename: George E
authors.initials: GE
authors.lastname: Magoulas
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Ourania N
authors.initials: ON
authors.lastname: Kostopoulou
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Garnelis
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece.
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Athanassopoulos
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Georgia G
authors.initials: GG
authors.lastname: Kournoutou
authors.affiliation: Department of Public Health, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Michael
authors.initials: M
authors.lastname: Leotsinidis
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Dinos
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece. Electronic address: dapapaio@upatras.gr.
authors.forename: Dionissios
authors.initials: D
authors.lastname: Papaioannou
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece. Electronic address: dimkal@med.upatras.gr.
authors.forename: Dimitrios L
authors.initials: DL
authors.lastname: Kalpaxis
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002701:Chloramphenicol / Q000737:chemistry*; D057075:Enzyme Assays; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015870:Gene Expression; D007700:Kinetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010796:Phthalic Anhydrides / Q000737:chemistry; D013095:Spermidine / Q000737:chemistry*; D013387:Succinic Anhydrides / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010796:Phthalic Anhydrides; D013387:Succinic Anhydrides; D002701:Chloramphenicol; C031801:succinic anhydride; D000123:Acetyltransferases; D013095:Spermidine; C043103:phthalic anhydride
keywords: Antibacterial activity; Chloramphenicol; Polyamine conjugates; Polyamine uptake system; Polyamines