Design, Synthesis & Anti-inflammatory Activity Of Erythromycin Derivatives

Erythromycin had been extensively used in the treatment of bacterial infections for over 40 years. Several semi-synthetic derivatives of erythromycin known as the 2nd generation macrolide antibiotics, which were developed during the 1980s, had enjoyed great clinical success due to their improved pharmacokinetic properties and attenuated gastrointestinal side effects as compared to erythromycin. Unfortunately, like erythromycin, the 2nd generation macrolide antibiotics had poor efficacy against macrolide-resistant bacteria. The intensive search for the 3rd generation macrolide antibiotics that overcame the problem of resistance had unveiled a new class of macrolide, termed ketolides. While much work had been concentrated on the elucidation of increasing potent antibiotics, a substantial amount of research had also been performed to find the agents with enhanced prokinetic effect. These investigations had lead to the discovery of motilides, which have potential for the treatment of gastrointestinal motility disorders. In addition to the anti-microbial and prokinetic effects, some novel activities of the erythromycin derivatives had attracted much attention as new therapeutic potentials. Many clinical studies suggested that erythromycin and its derivatives had favorable effects, which were chiefly due to their quite unique anti-inflammatory activities, in the patients with asthma, acute and chronic bronchitis, especially diffuse panbronchitilis (DPB). These unexpected successes had encouraged abundant investigations on the mechanism by which anti-inflammatory effects of macrolides occurred. Erythromycin as well as 2nd generation macrolides had been shown to affect a number of the processes involved in inflammation, including the oxidation burst in phagocyles, the migration of neutrophils, the production of various cytokines and so on. However, given the complexity of the inflammatory response and the multiple effectors involved in, the precise mechanisms of the actions still remained obscure.Although there were numerous reports in the past few years of macrolide antibioticshaving anti-inflammatory activity, little attention had been paid to the search for the novel erythromycin derivatives with increased anti-inflammatory activity, hi our effort to maximize the anti-inflammatory activity of erythromycin while to attenuate its antimicrobial and prokinetic effects, a series of macrolides (I~XV) were designed and synthesized. Among them, a 12-membered ring erythromycin derivative EY267108 (XV), which exhibited the significantly improved in vitro anti-inflammatory activity (30 times that of erythromycin) and the poor anti-microbial activity, was identified as a lead compound, hi order to optimize the lead compound and investigate the structure-activity relationships of the 12-membered ring erythromycin derivatives, four sets of target compounds (EMD-101-EMD-402) were designed. With the hopes of discovering a novel class of macrolides, we designed 10 dimers of erythromycin derivatives, such as "tail to tail" dimers (EMD-501-EMD-505), "head to head" dimers (EMD-506-EMD-509) and a "head to tail" dimer (EMD-510).Following the reported methodologies with only slight modifications, the target compounds I~IV and roxithromycin were prepared smoothly. VI-XH were obtained by N-demethylation with iodine and sodium acetate hi methanol. IV, a key intermediate for synthesizing dirithromycin, could be prepared under standard conditions employing NaBH/TiCl4 as a reducing agent. Since the routes described above suffered from some drawbacks, a mild and convenient procedure was developed for direct reduction of I to IV in the presence of NaBH4/ZrQ4 at room temperature with ultrasound activation. The cladinose moieties of erythromycin derivatives could be selectively removed upon the treatment with dilute hydrochloric acid in an aqueous solution. Applying this method to the preparations of Xin and XTV, inseparable complex mixtures were gotten. Thus, we carried out these reactions using DMF as the solvent at 50C, in which HC1 was...