Synthesis And Study Of The Tetrazole New Type Of Metal β-Lactamase Inhibitors And Hydroxamic Acid Derivatives Containing Isoxazole

This thesis consists of two parts. PartⅠ: Study on the synthesis of novel metallo-β-lactamase inhibitors in which tetrazole was contained; PartⅡ: Study on the synthesis of a novel class of isoxazole-based hydroxamate as PDF inhibitors.Withβ-lactam antibiotics by the wider use of the rapid spread of drug resistant. Metallo-β-lactamase type and number has been increasing serious impact on the merit of this kind of antibiotics. Traditional againstβ- lactamases measures are as follows: First, the search for new antibiotics and the other, and explore and make use of bacterialβstop - lactamase substances; Third, the combined use ofβ-lactamase sensitive and relatively stableβ-lactamase inhibitor; Fourth, the development of specificβ-lactamase inhibitors. For decades many experiments show that the development of specific inhibitors of metal has become a top priority. At present, with the characteristics of metallo-β- lactamase inhibitors are thioglycolic acid derivatives, thiosulfate pyridine carboxylic acid derivatives, such as Penicillium n-type oxide compounds, carbapenem compounds, cephalosporins ene and so on. Recently reported in the literature contains 3-n-butyl- 1-benzopyrazole-5-carboxylate diphenyl tetrazolium or contains 3-n-butyl-1-benzo pyrazole -5- ethane-ester diphenyl tetrazolium of metallo-β- lactamase inhibited, and its biological activity was studied, the findings showed that compounds containing tetrazole of metallo-β- lactamases have a certain effect.Tetrazole is a country with a wider use of functional groups. It is not only in Chinese medicine for lipophilic and carboxylic substituent substitute, but also as explosives, photographs and records information system, is widely used. In this paper, based on their improvement, where a benzene ring was replaced by an isoxazole ring, we synthesized a series of compounds to study their biological activity and the metallo-β- lactamase inhibitor.P-methylbenzaldehyde was used as the starting material, through 10-12 steps, including zinc catalytic 3+2 reaction of cyanobenzene and azide to form tetrazole, [3+2] cycloaddition of the aromatic cyano-oxide with alkyne to afford isoxazole, and followed by oxidation, esterification,hydroxylamination and finally got our target compounds..We also took benzothiazole hydroxamic acids as lead compounds, according to their structure-activity relationship as the PDF inhibitors, designed and synthesized a new type of hydroxamic acids in which isoxazole is contained.Benzaldehyde was used as the starting material, [3+2] cycloaddition was performed to afford isoxazole category,oxidation,esterification and hydroxyl amination were used to get final compounds. 15 new compounds were synthesized and their structures were conformed by NMR, ESI-MS, IR and elemental analysis. Vitro experiments showed that some of the compounds have antibiotic activity. And as a by-gaining, we find that these compound have good activity on hyperglycemic disease.