Synthesis And Bioactivity Of New Ketone Ester Derivatives

Macrolides antibiotics have been in clinical practice has been widely used, owing to its broad antimicrobial spectrum, convenience to take, safety, low side effects in clinical use and so on. However, the phenomena such as the abusement of antibiotics and the intensive emergence of antibacterial resistance against antibiotics has become more prominent. Therefore, the development of new macrolide antibiotics with high activity, low toxicity has become the main direction of the current study.Currently, the third generation of macrolide antibiotics-ketolide antibiotics such as telithromycin and Cethromycin is the main research direction of the entire field of macrolide antibiotics. These drugs have the following structural features:a3-keto group,11,12-carbamate, and an alkyl side chain.This research paper has the original innovation, which can provide a reference for the industrial production of telithromycin, enrich the new structure ketolide antibiotic compounds, and provide a new idea of the study of design and synthesis of new ketolide antibiotics.1. The novel preparation for telithromycin and its sulfur analoguesIn this study, the synthetic route operation of telithromycin and its sulfur analogue synthesis process has been optimized. They were was synthesized through a simple and feasible route with high yield and mild reaction conditions.2. Synthesis and biological activity of novel ketolide with11,12-quinoline contained aryl side chainsIn recent years, there are reports of liver toxicity with telithromycin, which limits its clinical application, we will adopt a series of new quinoline heterocyclic aryl side chains to modify the11,12-position of ketolide antibiotics, aiming to find the lead compounds with good antibacterial activity and no liver toxicity.An important intermediate for ketolide synthesis was obtained starting from commercially available clarithromycin. After reacting with different quinoline contained aryl side chains, a novel series of11,12-quinoline contained ketolides were synthesized. As the antibacterial activity, the compounds, such as Lei-29、Lei-27、Lei-42、Lei-26, have considerable biological activity with telithromycin against key macrolide sensitive and resistant pathogens.3. The exploration of ketolide antibiotics with new mother structureIn recent years the study of new mother structure in maternal ketolide antibiotics is rarely reported. This paper is also related to the exploration of ketolide antibiotics with new mother structure. Clarithromycin as raw material, the10,11-unsaturated carbonyl compound was prepared through a five-step reaction. The double bond was reacted with mCPBA to get the epoxy compound, with its relative configuration determined by NOE and HSQC. Then the transformation of the structure of the epoxy compound was carried out.Though we have not yet got the target compound through the synthetic route designed in this study, we provide a new way of thinking point for the future in-depth study of the ketolide antibiotics with new mother structure.