The Design And Synthesis Of Different Side Chains Introducing To Macrolide Mother Nucleus

Macrolide is a kind of alkalescence antibioties generated by Streptomycete, mainly used in infections of respiratory passage, genitourinary system and alimentary canal. Macrolide antibioties are important in clinic therapy. The first (represented by Erythrocin) and second generation (represented by Azithromycin) have been playing an significant role in respiratory, mycoplasma, chlamydia pneumonia and soft tissue infection.The 23s rRNA of 50s subunit of bacterial ribosomal contains peptidyl transferase center, which can catalyze the formation of peptide bond, and make the amino acid link to the ever-extending peptide chain to synthesize protein. Macrolide antibiotics can act on the nucleotide acid of V area in catalytic center, thus inhibiting bacterial protein synthesis. However, along with the widely clinical use of this antibiotic, serious drug resistance appeared correspondingly. Bacteria generate drug resistance mainly through target modifying, nuclear protein mutation, initiative excretion. Along with the continuous research of bacterial resistance mechanisms, more and more new macrolide antibiotic will be developed by structure modification.Recently the ketolides have been studied a lot. This kind of structure is not only stable to acid but also without induction drug resistance. It can combine with the first target of A2058 and the second target of A752 through 5-desosamine to display strong antibacterial activity.The research indicated that when the molecular polarity increased and molecular ionization degree degraded, the in-vivo activity of macrolide antibiotic increased. The side chain modification of C-11, 12 or C-6 can improve the pharmacokinetics feature. Removal of C-3 cladinosyl can overcome bacterial drug resistance mediated by macrolide antibiotic molecular.In order to improve the activity of macrolide antibiotic against resistant bacteria, on the basis of A2610 or A2655 as targets, the side chain had be introduced to 3- cladinosyl or 3- hydrxyl on macrolides, which may generate anti-drug-resistance-bacteria activity. In this paper, starting from erythromycin, 6-methyl-erythromycin as an intermediate was first synthesized, then different side chains were introduced to synthesis 5 target compounds. 3 target compounds were prepared from 6-methyl-erythromycin as starting material by the introduction of side chains in C-4″position of cladinose. 2 target compounds were obtained from 6-methyl-erythromycin as a starting material through the removal of 3-cladinose by hydrolysis, and then the modification of the hydroxyl groups at 11 and 12 positions into a 11,12-carbamate ring, last the introduction of side chains to 3-hydroxyl group. By changing the polarity of molecules, the penetration of medicine will rise, and the antibacterial spectrum will be widened.