Research On Design, Synthesis And Antibacterial Activity Of New Macrolide Derivatives

Macrolide antibiotics are so far the most active and most rapidly developing agents in anti-infection drugs and clinical research. They are just inferior toβ-lactam and quinolones anti-infection drugs in clinical use. The mechanism of action research indicated, the Macrolide antibiotics act on the 50S ribosomal subunits of bacteria, blocking the activity of peptidyl transferase in 50S subunits and consequently prevent the formation of peptide bond and inhibit the synthesis of protein and bring forth the antibacterial effect.In recent years, along with the structure modification work of erythromycin thoroughly developed, some second generation derivatives of erythromycin which have a high and long-term efficiency and a good bioavailability, such as roxithromycin, clarithromycin and azithromycin, have been obtained, which arosed deep attention of many countries in the research of new generation erythromycin derivatives which have more predominance such as anti-resistance and broad antimicrobial spectrum.The research object matter in this paper included as follows:1. QSAR research of macrolide antibiotics According to the known MIC data of macrolide antibiotics, using the computer aid drug design system Cerius2 software to create a best QSAR equation of macrolide antibiotics: log(1/MIC)=-0.471265-0.361728×"Rotlbonds"+0.107053×"Hbonddonor"+0.000386×"Apol"+0.145175×"LUMO"+0.010679×"Dipole-mag"r2=0.833,F-test=39.857,LSE=0.107,r=0.9132. Design, synthesis and structure identification of the derivatives of 3- substituted 15-membered azalides According to the result of QSAR, based on 9-deoxo-9a-aza-9a-9a- homoerythronolide A and 9-deoxo-9a-aza-9a-methyl-9a-homoerythronolide A, 22 derivatives of 3-substituted 15-membered azalides (II-1~II-22) derivatives were designed and synthesized. UV, IR, HPLC and 13C-NMR, characterized the intermediate and target compounds.3. One-pot synthesis of erythromycylamine derivatives under microwave irradiationSix compounds were one-pot synthesized from EMA and amines through the Leuckark reaction under microwave irradiation and their structures were confirmed by UV, IR and 13C-NMR. The best condition of the one-pot synthesis of derivatives of erythromycylamine under microwave irradiation was found by using the orthodoxy design method. The method was proved to be a more convenient and effective approach to synthesize erythromycylamine derivatives.4. Research of the synthesis of AzithromycinBased on erythromycin A, via oximation, Beckmann rearrangement, NaBH4 reduction and Eschweiler-Clarke methylation, Azithromycin was obtained. And detailed research to the synthesis process was learned.5. Antibacterial activity test in vitroThe antibacterial activity ( MIC ) of the 22 derivatives of 3-substituted 15-membered azalides(II-1~II-22) were tested by the tube dilution method. The compounds were screened by a number of bacteria, including S. aureus ATCC25923, S. pneumoniae ATCC49619, E. coli ATCC25922, S. aureus 8195 (resistant to EMA), S. pneumoniae 8220(resistant to EMA) and H. influenzae 8227, using EMA and Azithromycin as contrasts. Activity test in vitro show that compoundⅡ-2,Ⅱ-4 andⅡ-6 have good antibacterial activity, especially compoundⅡ-2 to erythromycin-resistant S. pneumoniae 8220, experiment shows that it not only has a better antibacterial activity than EMA and AZM, but also has a remarkable activity to G- bacteria such as E. coli ATCC25922 and H. influenzae 8227.The results of antibacterial test in vitro match well with the outcomes of the QSAR equation, which illustrates that the QSAR equation established has a high reliability and can guide the structure modification of macrolide derivatives. The characteristics and innovations of this research are as follows:1. Established QSAR equation of macrolide antibiotics for the first time and modified the structure of macrolide antibiotics according to QSAR.2. Based on 15-membered azalides, designed and synthesized 22 new derivatives of 3-substituted 15-membered azalides that have definite anti-resistance and effect to G- bacteria.3. First proposed and synthesized erythromycylamine derivatives by using microwave irradiation method, so as to shorten the reaction time greatly and enhance the production rate remarkably.