Design,Synthesis,and Antibacterial Activity Of A New Class Of Derivatives Of Macrolide Antibiotics

Macrolide antibiotics is a class of antibiotics which contains a special chemical structure of a lactone ring that consists of 11²2 carbons.These antibiotics have similar antibacterial effects.This thesis only involves 14¹6-membered macrolides which is the main part of macrolide antibiotics.Macrolide antibiotics are widely applied in field of medicine and pesti-cide due to its advantages such as wide antibacterial spectrum,good antibacterial activities,extensive tissue distribution,lighter side effect,and lower price.However,with the emer-gence of resistant bacteria,antibiotic resistance is becoming a prominent problem.People’s requirements cannot be satisfied by existing macrolide drugs.Development of new macrolide antibiotics is a brook no delay task.Now,domestic and foreign researches on macrolide anti-biotics are concentrated on the following directions:1)structural modification of compound with high antibacterial activities;2)improvement of pharmaceutical activities;3)formulation change;4)improvement of bioavailability.This thesis based on clarithromycin,modified its C-3 and C-11,12 structures,and finally obtained 15 new macrolide compounds whose struc-tures were confirmed by ¹H-NMR,¹³C-NMR,HRMS,etc.These target compounds were nev-er been reported before.1)Fourteen primary amine compounds 3aⁿ were synthesized through Gabriel synthesis.These amines provide new side chains for structural modifications of macrolide antibiotics.2)Based on clarithromycin,key intermediate 9 was synthesized through a series of steps including hydrolysis,oxidation,and dehydrogenation.Then 3a^j,and some other primary amines were introduced to 9,and finally 15 new macrolide compounds that were never been reported before were obtained.Those new compounds enriched the compound library of macrolides.3)In vitro antibacterial activities of the target products were tested.I4,I10,I11,and I12showed favorable antibacterial activities to sensitive strains.Especially,I10 had a minimum MIC of 0.25μg/mL for Staphylococcus aureus-sensitive strains,0.0625μg/mL for Staphylo-coccus epidermidis-sensitive strains,and 0.125μg/mL for penicillin-sensitive pneumococci.The MIC range for Streptococcus agalactiae is 0.0625⁰.125μg/mL,which is more than 128times that of erythromycin and clarithromycin.4)According to the test results and the structures of the compounds,the structure-activity relationships were analyzed,which mainly includes:a)When the terminal of side chain is a cycloalkane group,it is more advantageous to enhance the antibacterial activities of the com-pound if the distance from the terminal group to the nitrogen atom of carbamate ring is 2³carbon atoms;b)when the terminal of side chain contains a benzene ring and the distance from the terminal group to the nitrogen atom of carbamate ring is 3 carbon atoms,the intro-duction of a electron-donating group to the terminal benzene ring could be more favorable to improve the antibacterial activities than that of a electron-withdrawing group;c)when the terminal of side chain is a cycloalkane group,the introduction of heteroatoms may be benefi-cial to enhance the antibacterial activity of the compound;d)When the terminal of side chain contains a benzene ring,the position of the substituent on the benzene ring has a great influ-ence on the antibacterial activities of the compound.If the substituent is a nitro group,the pa-ra-substitution may be more advantageous than the meta-substitution to enhance the antibac-terial activities.