Design, Synthesis And Biological Activity Of 3-O-Carbamate Macrolide Derivatives Against Resistant Bacteria

More than 20 kinds of macrolide antibiotics, which have been used since the early 1950s, have been playing an important role in clinic. Macrolide antibiotics, with little anaphylactic response, have good antibacterial activitiy against Gram-positive bacteria, some Gram-negative bacteria, and mycoplasma. With the extensive use of the antibiotics, especially abuse, the serious problem of bacterial resistance has happened in clinic, which results in a decrease in curative effect, and even no effect.Macrolides can bind to the peptidyl transferase center in domain V of the 23S rRNA in 50S subunit of bacterial ribosome and exert their antibacterial activities by inhibiting protein synthesis of bacteria. In addition, there are many mechanisms of the bacterial resistance in bacteria, such as methylation of Ribosomal RNA, efflux and mutations in Ribosomal Proteins and Ribosomal RNA.In order to enhance the activities of macrolides against resistant bacteria, we designed and synthesized a novel series of compounds through the introduction of different carbamate side chains in C-3 hydroxyl group. In this paper, we synthesized 11 novel 3-O-carbamate macrolides using the clarithromycin as a starting material by the introduction of different side chains in five steps. The structures of these compounds were confirmed by MS, IR, ¹HNMR, ¹³CNMR. Also we found a new synthetic method of these compounds.The in vitro antibacterial activities of these compounds were assessed. The results showed that most of these compounds had good activity against susceptive bacteria. Especially compounds c and d had the same activities against S. pneumoniae and S. pyogenes as erythromycin, clarithromycin and azithromycm, and more potent activities agnist S. aureus than erythromycin and azithromycin. Meanwhile, most of these compounds had good activity against resistant S. pneumoniae A22072 (mefA) and weak activity against resistant S. pneumoniae (ermB) and S. pneumoniae (ermB+ mefA).Among these derivatives, compounds with hydroxyl group or linear side-chains can easily bind to the target sites in bacteria through forming hydrogen bonds, producing good antibacterial activity, particularly activity against resistant S. pneumoniae (mefA). In the future, we will synthesize more compounds through the introduction of different carbamate side-chains having hydroxyl group, amine group and carbonyl group in C-3 hydroxyl group. Therefore, we hope to find novel macrolide antibiotics with more potent anti-resistant activity and broader antibacterial spectrum.