.3 - Keto-6-o-methyl Erythromycin -9 - Substituted Oxime Derivatives And 7 - Substituted Pyrrolidinyl Quinolone Derivatives And In Vitro Antibacterial Activity,

This dissertation contains two parts.The first part: synthesis and in vitro activity of 3-keto-9-O-substituted oxime derivatives of 6-O-methyl erythromycin A.Recently years, many studies about macrolides have been done. And the discoveries concerning the structure-activity relationships (SAR) of erythromycin analogues has led to a new subclass of macrolides-the "ketolide" class, in which the 3-cladinosyl sugar residue has been replaced by a ketone functionality. These ketolides have been shown to have good in vitro and in vivo activity against erythromycin-susceptible Gram-positive organisms, as well as against organisms with inducible resistance against erythromycin.We decided to prepare a compound having an oxime group directly attached to the macrolactone ring at C-9, thus generating a series of 9-oxime derivatives of the ketolide. We expected that these derivatives would also demonstrate improved activity against resistant organisms.To synthesize 3-keto-9-O-substituted oxime derivatives of 6-O-mthyl erythromycin, we have designed four syntheric routes, in which the route 3 and the route 4 are new approaches. In route3, our synthetic strategy, which prepare the wanted compounds from 6-O-methyl erythromycin, involves producing 6-O-methyl erythromycin-9-oxime, protection, hydrolysis, oxidation, deprotection and addition reaction. However, the route 4, which prepare the wanted compounds from erythromycin A, include 7 steps - oximation, protection, methylation, hydrolysis, oxidation, deprotection and addition reaction. Finally, we got 12 unreported compounds and intermediates, among of the 22 obtained compounds. And their structure were elucidated by IR, ¹³CNMR and MS spectra.The antibacterial activity of 11 new compounds were tested in vitro against both erythromycin-susceptible and erythromycin-resistant organisms. Among of them, 8 compounds have some antibacterial activity against some erythromycin-resistant organisms.The second part: synthesis and in vitro activity of 7-substituted pyrrolidine derivatives of quinolone.Fluoroquinlone is one kind of the most effective clinical antibiotics. But they have low activity not only to anaerobes, mycoplasmas and chlamydozoans but also to Gram-positive bacteria. So the second part of the dissertation focused on the new quinolone drugs, which would have higher activity to those pathogens. According to the known structure-activity relationship, quinolone , which contain a 3-amino-pyrrolidine or 3-aminomethyl-pyrrolidine at the C-7 position such as tosufloxacin and gemifloxacin, can provide improved Gram-positive antibacterial activity, while retaining the good Gram-negative activity. At the same time, they have moderate activity against anaerobes, mycoplasmas and chlamydozoans too. According...