ABSTRACT
A total synthesis approach of CS-E oligosaccharides was established and a series of derivatives were synthesized. These oligosaccharides were evaluated for a glycosaminoglycan (GAG)-binding protein interaction against cytokines, midkine, and pleiotrophin, by surface-plasmon resonance (SPR) assay. The binding epitopes of oligosaccharides to midkine were mapped using a saturation transfer difference (STD) NMR technique. The groups on the reducing end contributed to binding affinity, and should not be ignored in biological assays. These findings contribute to the structure and activity relationship research and a foundation of understanding that will underpin potential future optimization of this class of oligosaccharides as pharmaceutical agents.
Subject(s)
Chondroitin Sulfates , Oligosaccharides , Chondroitin Sulfates/pharmacology , Chondroitin Sulfates/chemistry , Chondroitin Sulfates/metabolism , Midkine/metabolism , Protein Binding , Oligosaccharides/chemistryABSTRACT
A series of novel 4â³-O-desosaminyl clarithromycin derivatives with 11, 12-arylalkyl side chains was synthesized by coupling 6-deoxy-desosamine donors (18, 19) with 4â³-OH of compounds 5a-c. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive and resistant pathogens, and compounds 21d and 21e displayed significant improvement of activities against resistant pathogens.
Subject(s)
Amino Sugars/chemistry , Anti-Bacterial Agents/chemical synthesis , Clarithromycin/analogs & derivatives , Clarithromycin/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Clarithromycin/pharmacology , Drug Resistance, Bacterial , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of novel 5-O-(4',6'-O-dimodified)-mycaminose 14-membered ketolides were assessed for their in vitro antibacterial activities against a panel of sensitive and resistant pathogens. Compound 1 and compound 2, two ester analogs, showed the best antibacterial activities against several macrolide-sensitive and macrolide-resistant strains. These results indicated that introducing ester to 6-OH and a small volume ether substituent to the 4-OH of mycaminose could improve the antibacterial activities of ketolides.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Ketolides/chemistry , Ketolides/pharmacology , Bacteria/drug effects , Molecular StructureABSTRACT
A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32. The corresponding targets 7a-n, 33b, and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens.
Subject(s)
Anti-Bacterial Agents/pharmacology , Haemophilus influenzae/drug effects , Ketolides/pharmacology , Quinolines/pharmacology , Staphylococcus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Azithromycin/pharmacology , Dose-Response Relationship, Drug , Drug Resistance, Bacterial , Ketolides/chemical synthesis , Ketolides/chemistry , Methicillin Resistance , Microbial Sensitivity Tests , Molecular Structure , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Some novel josamycin derivatives bearing an arylalkyl-type side chain were designed and synthesized. By HWE or Wittig reaction, 16-aldehyde group of josamycin analogs were converted into unsaturated carbonyl compounds. They were evaluated for their in vitro antibacterial activities against a panel of respiratory pathogens. 8b and 8e exhibited comparable activities against a panel of respiratory pathogens, especially to resistant ones in the series of desmycarosyl josamycin analogs. Among of all the target molecules, 21 showed the best antibacterial activities.