Design, Synthesis And Biological Activities Of 14-Numbered Macrolide Derivatives Against Resistant Bacteria

Since the early 1950s,More than 20 kinds of macrolide antibiotics that have been used in clinic,which have been playing an important role in clinic.Macrolide antibiotics,have good antibacterial activitiy against Gram-positive bacteria,some Gram-negative bacteria and mycoplasma,and they have lower anaphylactic response than aminoglycosides,tetracyclines and polypeptideetc.however,With the extensive use of the antibiotics,especially abuse,the serious problem of bacterial resistance happened in the clinic,which results in a decrease in curative effect,and even no effect.The macrolides' mechanism of action is that they 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,besides,there are many mechanisms of the bacterial resistance to macrolides.The main mechanisms are:efflux,methylation of Ribosomal RNA and mutations in Ribosomal Proteins and Ribosomal RNA.In order to enhance the activities of macrolides against resistant bacteria,we synthesized a novel series of compounds through the introduction of different carbamates in C-4″hydroxyl group and reserving the C-2′hydroxyl group which is the essential group of antibacterial activity.In this paper,we synthesized 22 novel 4″-O-Carbamate macrolides using the erythromycin and 6-methylerythromycin as starting materials by the introduction of different side chains in C-4″hydroxyl group in four steps.The structures of these compounds are confirmed by MS,IR,¹HNMR,¹³CNMR.The in vitro antibacterial activity of these compounds was assessed against both erythromycin-susceptible and erythromycin-resistant bacteria.We find that most of these compounds have good activities against susceptive bacteria andresistant S. pneumoniae(mefA).The activity is improved against drug-resistance S. pneumoniae(ermB)and S.pneumoniae(ermB+mefA).Among these derivatives,compounds with hydroxyl group or linear side-chains, possessed the best antibacterial activities,particularly against erythromycin-resistant S. pneumoniae(mefA).In the future,we will synthesized more compounds through the introduction of different carbamates which have hydroxyl group,amide group and carbonyl group in C- 4″hydroxyl group,in order to find novel macrolide antibiotics with more powerful anti-resistant activities and broader antibacterial spectrum.