ABSTRACT
Novel modifications of the desosamine sugar of 14- and 15-membered antibacterial macrolides, in which the desosamine was fused with N-substituted-1,3-oxazolidin-2-ones, were developed in order to completely suppress antibacterial activity and make them promising agents for other biological targets. The synthesis of such bicyclic desosamine derivatives, especially 1,3-oxazolidin-2-one formation, was optimized and conducted under mild conditions without a need for protection/deprotection steps for other functional groups. A focused series of novel desosamine-modified macrolide derivatives was prepared and their antibacterial activities tested. It was shown that these macrolide derivatives do not possess any residual antibacterial activity.
Subject(s)
Amino Sugars/pharmacology , Anti-Bacterial Agents/pharmacology , Amino Sugars/chemistry , Anti-Bacterial Agents/chemistry , CyclizationABSTRACT
Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Azithromycin/chemical synthesis , Macrolides/chemical synthesis , Microsomes, Liver/drug effects , Pneumococcal Infections/drug therapy , Streptococcus pneumoniae/drug effects , Administration, Oral , Animals , Anti-Bacterial Agents/pharmacokinetics , Azithromycin/analogs & derivatives , Azithromycin/pharmacokinetics , Biological Availability , Carboxylic Acids/chemistry , Crystallography, X-Ray , Drug Stability , Esters/chemistry , Humans , Injections, Intravenous , Macrolides/pharmacokinetics , Male , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Models, Molecular , Pneumococcal Infections/microbiology , Rats , Rats, Wistar , Streptococcus pneumoniae/growth & developmentABSTRACT
In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.