Design, Synthesis And Antibacterial Activities Of Erythromycin Derivatives

The synthesis and structure-activity relationship (SAR) of the derivatives of macrolide antibiotics were studied in this dissertation.Since being discovered macrolide antibiotics such as erythromycin A have played a key role in the treatment of bacterial infections. Interest in 14-membered ring macrolides was renewed in the 1980s. Erythromycin however is quickly degraded into inactive products in the acidic medium of the stomach. This is the reason why the first success in the macrolides field came from the improvement of erythromycin pharmacokinetics through the synthesis of the more acid-stable derivatives roxithromycin, clarthromycin, and 15-membered ring macrolide azithromycin. The chemical modifycations have been made on the macrolactone and 6-OH part of erythromycin.However all these drugs have poor efficacy against MLS_B-resistant strep-tococci. Now, the intensive search for the third generation macrolide antibiotics that overcome the problem of resistance had unveiled four classes of macrolides, termed ketolides, 2,3-anhydrolides, acylides, and erythromycylamine 4"-carbamates. The chemical modifycations have been made on the cladinose, 6-OH, 11-OH, and 12-OH part of erythromycin.For further study of the SAR, four types of macrolide derivatives were designed via modification of the leading compound which is erythromycin A. Seventy-nine new compounds Were synthesized and all of them have not been reported in literature. Their chemical structures were characterized by of ¹³C-NMR and MS.With erythromycin A as starting material, a new synthetic route was developed for the synthesis of compounds of erythromycin amidines and erythromycin amidoximes.Followed the reported methods with some modifications, the target compounds Z-54^Z-72, acylide derivatives of clarthromycin and 4"-carbamate derivatives of clarthromycin, were prepared.A route was designed for synthesis of acylide derivatives of erythromycin amidoximes and the compounds Z-73～Z-79 were prepared. Antibacterial activities in vitro of these compounds were evaluated with serial dilution test. The results show that most of them have antibacterial activities. The antibacterial activities of compounds Z-46, Z-51 were comparable to erythromycin A.Some new finding in the structure-activity relationship of these compounds was discussed, and benefit the further study in this field.