The Studies On Synthesis Of Telithromycin And The Novel Ketolide Compounds, The Determination Of Their Antibacterial Activities And The Study On Structure-activity Relationships

The rapid development of antibioitics-resistant Strains such as MRSA MRPA PRSP VRE ESBL AMPC MBL have caused difficulty to clinical treatment in recent years.As one of common bacterial species,Streptococccus Peumoniae is growing in a trans-normal rapidity,moreover the abuse of antibioitics in clinic caused muti-drugs resistance.Bacterial community-acquired respiratory tract infections(CA-RTS)caused by resistant or muti-drugs resistant S.Peumoniae, various pattern of penicillins,amcrolides,trimethoprim—sufamethoxazole,tetracycline, furoquinolone and chloramphenicol resistant isolates is prevailing,the infections in clinical associated withβ-lactam resistance in H.influenzae and M,catarrrhalis,muti-drugs resistant methiciliin-resistant Straphylococcus Aureas is also becoming a serious clinical problem.Many antibiotics or antibacterial-drugs many decrease the efficacy in a high dgree,thus,all the pharmaceutists are seeking new antibiotics of new structure.Erythromycin as a standing macrolide antibacterial drug has notable advantages such as low consume,broad antibacterial spectrum,pharmaceutical activities and oral adminstration,has been used in clinically sine 1950's,it applys to treatment of community-acquired respiratory of the respiratory tract and skin or soft tissues infections,up to date,it remains the reference of the macrolides.Since 1980s,,some studies were carried through to decrease the side-effects and to increase the acid stability,and the bio-availability,reduce the gastrointestinal side effects,and several valuable new drugs or compounds in the practice of clinic,Rexithromycin,Clathromycin, Azithromycin and Dithromycin came into the market successfully.Since their unique therapy efficacy,research in the domain ofmacrolides becomes the most active point.Telithromycin is a novel structure macrolide,like Cethromycin.Named ketolide for it derived from 14-memberd-ring macrolide and being characterized by a carbonyl group at the C-3 position. It inhibit bacterial protein synthesis by bang to the 50s ribosomal subunit in domain V of the 23SrRNA and causing premature dissociation of the peptide dttring translation.It mainly inhibit gram-positive bacterial resitant and susceptibe(macrolide susceptible and resitant),such as S. Peumoniae,S.Aureas,S.Epiderimidis,S.Pyogenes,etc,also it can inhibit some negative aerobes, and achieve a high degree stability,good pharmacodyamics activity.Telithromycin was appreciated to be a potent antibiotics.Telithromycin has been successfully synthesized through two new synthetic routes.Another gave us a valuable thought in preparation of Telithromycin.Based on the literature method,the first route made several modification in some steps;it is a good research for the synthesis progress; The second method was a modified method to synthesis,absorbing the advantage of Neber Reaction and the first method,it is a new method which has not been reported in the literatures too.In order to seek new macrolides that have better activity and study the structure-activity relationship(SAR),three series macrolides or ketolides have been synthesized,the derivatives of 3-ketolide-6-methoxy-11-N-[3-[(N-aryl or alkyl)]carbamates-11-N,12-O-cycliccarbamate erythromycin A,and the 3-ketolide-6-methoxy-2'-(N-aryl or alkyl)carbonate erythromycin A, and many intermadites of macrolides and ketolides were prepared in the progress of synthesis of the new compounds.In vitro anti-bacterial activities of 11 new compounds have been measured.The compounds of 3-ketolide-6-methoxy-11-N-[3-[(N-aryl or alkyl)]carbamates-11-N,12-O-cycliccarbamate erythromycin A proved to have good activities in inhibiting MSSA,MIC₉₀are low than erythromycin A and Azithromycin.The MIC₉₀of CA series for resitant MSSA are low 100 times than e rythromycin A and Azithromycin,and low 2 times for susceptible MSSA.The MIC₉₀of most compounds for MSSE are low 2～16 times than erythromycin A and Azithromycin,but high than Telithromycin.3-ketolide-6-methoxy-2′-(N-aryl or alkyl)carbonate erythromycin A tested to have poor activities.Structure-activity relationship(SAR)result;3-ketolide-6-methoxy-11-N-[3-[(N-aryl or alkyl)]carbamate-11-N,12-O-cycliccarbamate erythromycin A show good activities for they are analogous compound,of Telithromycin,(N-aryl)groups and substituted benzene by proved electronic groups are essential to enhance gram-positive bacteria activity. 3-ketolide-6-methoxy-2'-(N-aryl or alkyl)carbonate erythromycin A have little activity for the 2'-OH was protected.43 compounds and intermediates have been synthesized in the studies,of which 10 compounds were previously unreported,and 11 new objective com.pounds have been obtained. The structure was verified by ¹H-NMR,¹³C-NMR,MS,IR,etc.