Synthetic Process Study Of Telavancin And Synthesis And Antibacterial Activities Research Of Telavancin Analogues

There are two parts in my dissertation:Part 1:Synthetic process study of Telavancin.Telavancin was developed by Theravance Inc. In 2009, and is the first semisynthetic glycopeptide antibiotics approved by FDA for treatment of complicated skin and skin structure infections caused by susceptible Gram-positive bacteria. Telavancin is derivative of vancomycin by the addition of a lipophilic decylaminoethyl substituent on the vancosamine amino group and a hydrophilic (phosphomethyl)aminoethyl moiety on one of the phenylglycine residue. Considering low cost, easy operation, low pollution, high yield and so on, we have carried out synthetic process study of telavancin using decyl alcohol as the starting material. After methanesulfonylation, nucleophilic substitution with ethanolamine, Fmoc protection, and Parikh-Doering oxidation, N-(9-fluorenyl-9-methoxycarbonyl) decylaminoethyl acetaldehyde (5) was obtained as the key intermediate. Vancomycin hydrochloride and intermediate 5 were then subject to reductive amination reaction, Fmoc deprotection, and Mannich reaction to give the target product telavancin.For synthesis of N-(9-fluorenyl-9-methoxycarbonyl) decylaminoethyl acetaldehyde, we have optimized the ratio of material and the solvent of the process of purification to achieve better yield. But the most important reactions of the process are reductive amination and Mannich reaction. We have deeply studied reductive amination and Mannich reaction and optimized the reaction conditions and process parameters to improve the efficiency of the reaction, controlled the side reactions of reductive amination, optimized Mannich reaction temperature and the ratio of material. The overall yield is 46% based on starting material vancomycin.Part 2:Synthesis and antibacterial activities research of Telavancin analogues.Glycopeptide antibiotic was regarded by experts as the "humanity against intractable drug-resistant strains of the last line of defense" and "ace antibiotics". With the widespread use of vancomycin, the gradual emergence of vancomycin-resistant gram-positive bacteria, in particular vancomycin-resistant Enterococci and Staphylococcus aureus. Human life and health is seriously threatened, therefore, the development of new glycopeptide antibiotic is imperative. Structural modification of natural glycopeptide can further improve antibacterial activity. We select three modification strategies for the structure of vancomycin, introducing a hydrophobic side chain at vancosamine,C-terminal of heptapeptide amino modification and introducing glycosylation at the aromatic ring of 7-position. Then,32 telavancin analogues (Van001-Van032) were designed, synthesized and their antibacterial activities against Staphylococcus aureus and Enterococcus faecalis were tested in vitro by using some antibacterial activity assays. There are five compounds (VanOll, Van013, Van017, Van024, Van025) exhibited strong antibacterial avtivities against Newman strain (MIC< 0.0625μg/mL), three compounds (Van015, Van017, Van025) exhibited strong antibacterial avtivities against Mu50 strain (MIC≤0.125 μg/mL), and four compounds (Van011,Van013, Van017, Van025) exhibited strong antibacterial avtivities against Enterococcus faecalis (VanB) (MIC≤0.125μg/mL). The antibacterial activities of the above telavancin analogues were significantly better than that of vancomycin or telavancin. We discussed and summarized the structure-activity relationship of telavancin analogues, and further pharmacological evaluation is in process for screening more ideal drug candidates. This work provided useful information and contributed to find novel scaffolds for developing new glycopeptide antibiotic.