Design, Synthesis And Antibacterial Evaluation Of 11-O-(2-(Arylalkylamido) Ethyl) Carbamoyl Clarithromycin Analogs

Macrolides are weak basic and lipophilic compounds containing a fourteen to sixteen membered lactone ring.They have the broad antibacterial spectrum and distinct curative effects, and have been widely used for the treatment of clinical infectious and non-infectious disease. However, the abuse of antibiotics makes the drug-resistant problem more and more serious. In order to optimize the pharmacokinetic properties, improve the activity against resistant bacteria, reduce the development of inducing drugresistance and side effects of drugs, researchers modify the structure of macrolide constantly. So, they have developed three generation macrolide products.New generation ketolide compounds, such as cethromycin and telithromycin, have good antibacterial activity in vitro. The arylalky side chain attached to C-6 or C-11,12 positions has an interaction with the bacterial ribosome, so they can effective against resistant bacteria. Based on the research results above, we synthesized compounds of series A and series B by introducing a series of carbamate side chain at the C-11 position of clarithromycin or modifying the C-4"hydroxyl group of C-3 cladinose. We changed the length and the terminal substituent of the side chain to examine the influence of combined modification on antibacterial activity.We explored the synthetic route and established the preparation, separation and purification methods of clarithromycin derivatives. In addition, the structures of target compound were confirmed by MS,’HNMR spectrum. Afterwards, we adopt broth microdilution method to evaluate the in vitro antibacterial activityof the compounds synthesized above and summarized the antibacterial activity and structure-activity relationship.The results of antibacterial activity against susceptible strains showed that all the compounds tested were less potent than the controlls. However, they had better activity against gram-positive bacteria than against gram-negative bacteria.The antibacterial activity of series Acompounds were better than that of series B compounds.Compound A7 and A8 had the most improved activity against susceptible Staphylococcus aureus with their MIC value of 0.5 μg/mL. The MIC value of compound A3, A7 and A8 against susceptible Streptococcus pyogenes was as low as 0.03 μg/mL. The MIC values of compounds against Escherichia coli and Pseudomonas aeruginosa were 32μg/mL and 64μg/mL, respectively.The results of antibacterial activity against resistant strains showed that all the compounds had significantly enhanced activity against erythromycin resistant S. pyogenes, ermB type resistant Streptococcus pneumoniae and ermB+ mefA type resistant S. pneumoniaecompared to controlled drugs. Especially, the antibacterial activity of all the compoundsagainst ermB type resistant S. pneumonia was the best. Besides, the in vitro antibacterial activity of all the compounds against mefA type resistant S. pneumoniae was slightly weaker than controlled drugs and their antibacterial activity against methicillin-resistant S. aureus was far lower than controlled drugs. Interestingly, the antibacterial activity trend of compound against resistant strains was just on the contrary with susceptible strains. The antibacterial activity of series B was better than that of series A. In addition, compounds B3 exhibited 32-fold higher activity against erythromycin resistant s. pyogenes than controlled drugs with their MIC values of 4μg/mL. CompoundsB7 and B8 had the most improved activity against ermB type resistant S. pneumoniae with their MIC values as low as 1μg/mL, showing 128-fold higher activity than controlled drug. The MIC value of A8 and B10 against mefA type resistant S. pneumonia was 1 μg/mL, which was 4-fold lower than controlls. Compound A1 had potent activity against ermB+ mefA type resistant S. pneumoniae with MIC value of 8μg/mL, which was 16-fold higher than that of controlled drugs.We concluded the following structure-activity relationship based on the MIC analysis of series A and B compounds:the introduction of carbamate side chains to C-11 position of clarithromycin can improve antibacterial activity of compounds against ermB type resistant S. pneumoniae and the antibacterial activity of all the compounds against susceptible strains are relatively weak when compared with the controlls. However, A8 has significantly enhanced activity against susceptible strains and its 10,11-dehydration modification method is better than the modification method at the C-11 position. The C-4" modification can significantly enhance antibacterial activity of compounds against resistant strains, but reduces their activity against susceptible strains. Therefor modification inC-4" position is critical to improve their activity against resistant strains. The length of the side chain has no distinct effect on antibacterial activity and the type of terminal substituent has an influence on activity in some extent in which compounds with electron-withdrawing substituent have more potent activity than that with the electronic substituent.