Synthesis And Structure - Activity Relationship Of Tetradecanone Lactone Derivatives Modified With 5 - Position Dimethylamine

Macrolide antibiotics have been widely utilized to treat bacterial infections for their broad antimicrobial spectrum, convenient using, safety and low toxicity. However, bacterial resistance to macrolide antibiotics has become increasingly prevalent over the past decades and reports about the resistant pathogens are growing fast. It greatly interests the researchers to overcome the problem.The5-O-desosamine residue is considered to be indispensable for the antibacterial activity. As the major origination of the binding energy with the ribosome, slight modifications to the5-O-desosamine might result in change of antibacterial activity. Therefore such researches contribute to understand the action mechanism of desosamine from different perspectives and to find chemical structures effective to the resistant pathogens.16-Membered macrolides have a mycaminose-mycarose disaccharide at the C-5position, which is oriented similarly to the5-O-desosamine of14-membered macrolides. Furthermore the mycarose reaches to the peptidyl transferase center (PTC), and directly inhibits peptide bond formation. However,14-membered macrolides with a shorter5-O-desosamine could not inhibit peptide bond formation, but can block elongation of nascent peptides.Based on the structure of the16-membered ketolides, we modified C-4’position of14-membered ketolides. We presumed if suitable substituent ould be introduced to the C-4’ position of5-O-desosamine they probably have different effects on the interaction between the desosamine and the ribosome binding site.This dissertation is original and creative, and it greatly enriched the structures of macrolide antibiotics. Moreover, such structural modification helped to better understand the mechanism of the macrolide-ribosome interaction and to find new effective antibiotics against resistant pathogens.1. Constructing the method of modifying the C-4’ position of14-membered macrolide.Adopting the convergent synthetic strategy, we synthesized the4-O-benzyI desosamine analog in9steps using methyl-a-D-glucopyranoside as the starting material, and prepared the5-hydroxyl macrolide acceptor in9steps using clarithromycin as the starting material, respectively. Then the4-O-benzyl desosamine was coupled to the5-hydroxyl macrolide acceptor succesfully.2. Synthesis and SAR study of5-0-4’-modified desosamine14-membered ketolideAfter the glycosilation of the5-hydroxyl macrolide acceptor, three series of4’-modified14-membered ketolides were synthesized:4’-carbamate derivatives,4’-amide derivatives and the4’-arylalkyl amine derivatives. Their antibacterial activities were tested and the SAR were analysed and summarized.3. Glycosilation of the3-hydroxyl of14-membered macrolide with the4-O-benzyl desosamineBecause of the importance of the desosamine in the macrolide antibiotics and the symmetry of the structure of the macrolide, we tried to couple the4-O-benzyl desosamine to the3-hydroxyl of14-membered macrolide. We tried many different methods and failed to obtain the target compouds, however, this process did help to our understanding and application of the glycosilation methods.