Design And Synthesis Of Novel Antibacterial Erythromycin

Macrolide antibiotics have been widely utilized to treat severe bacterial infection in clinical.With the widespread use of macrolide antibiotics,bacterial resistance has become increasing prevalent.Therefore,a large number of scientific research workers foucs on finding a new target basis on the study of macrolide and ribosomes mechanism.Based on the previous SAR,we design a series of compounds,and study the quinolones reactions for the first time,which provide new ideas and directions for the future research.The main modified positions are C-3,C-6,C-9,C-11,C-12,and C-11 and C-12 are mainly carbonate structure.Because of the fluorination at the C-2 position can ensure the stability of carbonyl of C-3 and improve the antibacterial activity,we design the compound of 2-F ketolides 9 to study the effect of macrolides which containing amino group.To study the effects of epimerization at 3-OH and the effects of interaction with multiple binding sites located in the bacterial ribosome on antibacterial activity,we design compounds 11 which C-3 and C-9 form the double-target combination: and the compound 19 which C-3 and C-6 form the double-target combination.And also design the compound which C-6 and C-9 form the double-target combination.The compound has good antibacterial activity which C-3 linkes with fluoroquinolones,we design compounds which C-3 links with fluoroquinolones,and the C-9 is modified to screening compound with better activity.The important intermediate in design routes: 7 and 25 are synthesized different from the previous route,which has the advantages of simple operation and high yield from 42% to 52%-56%.The synthesis route also involves the reaction which has higher non-water standard and the separation of compound which has higher polarity,and provids theoretical guidance for silimar experiments in the future.The results of the active test shows that the compound 9 containing aminopyridine posses better activity against streptococcus pneumonia,staphylococcus aureus,streptococcus pyogenes,moraxella catarrhalis and haemophilus influenza.The antibacterial activity of compound 11 and 19 is lower than clarithromycin and azithromycin,although they have the 2-F and double side-chain.Thus we can speculated that epimerization of C-3 is detrimental to the antibacterial activity.