Studies On Design, Synthesis And Biological Activities Of Macrolide Derivatives Against Resistant Baeteria

Erythromycin A is the most commonly used macrolide antibiotics on clinical, it is primary for the treatment of skin diseases, sexually transmitted diseases, respiratory infections and soft tissue infections and other diseases caused by Gram-positive bacteria. But there is also a narrow antibacterial spectrum, poor acid stability and cross-resistance to other shortcomings, makes its application limited to a certain extent.In recent years, chemical modification of the erythromycin derivatives to search for new effective macrolides against resistant bacteria has been made significant progress. From the perspective of the chemical structural modification to enhance activity against resistant bacteria, there are four classes of macrolides termed Ketolides, Acylides,4"-Carbamates and Anhydrolides.Macrolides bind to the peptidyl transferase ring. The Cladinosyl of the C-4 "-hydroxy is at the entrance. It is expected that the C-4"-hydroxy by the structural modification with carbamoyl can enter the channel. The bacterial 50S ribosome subunit A～P bind nucleotide targets, thus to play a better antibacterial activity. Acylides is a 3-O-carbamoyl derivative of macrolide. Acylides bind to the peptidyl transferase exit of the 2610 combination to perform its antibacterial activity, and at the same time they can solve the induction of bacterial resistance problems and improve the drugs membrane permeability to increase their activity.Carbamoyl is the most extensive introduced group on structural modification of macrolides. It can not only improve the fat solubility of drugs, but also it is not easy to be hydrolyzed by esterase of the body, thus prolonging the half-life of drugs.6,11-Di-O-methylerythromycin A possessed higher acid-stability compared to erythromycin A, exhibited excellent in vitro and in vivo antibacterial activities against Gram-positive bacteria and Mycoplasma pneumoniae. We choose chlorotrimethylsilane as the protection agent to synthesis it. The structure was confirmed by MS,1H NMR and 13C NMR and its content was determined by HPLC. 6,11-Di-O-methylerythromycin A was identified as a lead compound in this study.In order to enhance the activities of macrolides against resistant baeteria, we designed and synthesized two novel series of compounds through the introduction of different carbamate side chains in C-4"-hydroxyl and C-3-hydroxyl group. We received 25 new 4 "-carbamates(compoundⅢ-4) and 26 new 3-O-carbamates (compoundⅣ-4) derivatives. The structures of these compounds were confirmed by MS, IR,1H NMR and 13C NMR. Also we found a new synthetic method of these compounds.The above synthesized compounds, as well as erythromycin, clarithromycin and azithromycin as reference compounds, were tested for in vitro antibacterial activity against three strains of S. aureus and two strains of each Strep. pneumoniae and H. influenzae. The activities are reported as minimum inhibitory concentrations(MICs) that were determined by both two fold dilution assay. The results obtained demonstrated that there were four compounds showing antibacterial activities against tested strains among the 25 new 4 "-O-carbamates and compound(Ⅲ-4y) showed better activities. Also there were six compounds showing better antibacterial activities against tested strains among the 26 new 3-O-carbamates and compound(Ⅳ-4p) showed better activities too.The two series of carbamates designed and synthesized with aryl or heterocyclic carbomyl of 6,11-di-O-methylerythromycin A showed better activities in vitro than the alkyl and alkoxy substituted alkyl carbomyl derivatives.