Synthesis And Activity Evaluation Of Two New Classes Of Antibacterial Analogues

In recent years,the emergence and widespread spread of multiresistant Bacteria(MRBs)has led to a steady decline in the clinical efficacy of existing antibiotics,posing a great challenge to public health.The development of new antimicrobial active drugs is the most favorable weapon to meet this challenge,therefore,it is urgent to develop antimicrobial drugs with new structures and new mechanisms of action.This thesis is centered on the design,synthesis and evaluation of antibacterial activity of novel cephalosporins and the synthesis and evaluation of antibacterial activity of natural isopentenyl flavonoids.Four main chapters are included as follows.The first chapter is a preface,which briefly outlines the current status of bacterial infections,the classification and antibacterial mechanism of antibiotics,and the resistance mechanism of bacteria.Combined with the main content of this thesis,it proposes that natural products are an important source of antibacterial drugs and briefly describes the research content of the thesis.In the second chapter,7β-amino-3-[(1-methyl-1H-tetrazol-5-yl)sulfanylmethyl]-3-cephem-4-carboxylic acid(7-TMCA)was used as the starting material,which was protected by dibenzodiazomethane,condensed and oxidized,and added with propargyl alcohol in the presence of acid-binding agents,followed by the removal of the protecting group with Gerard’s reagent to obtain intermediate XXTB-6.The 7-β side chain was introduced to obtain 16 novel cephalosporins.The in vitro antibacterial activity of the 16 newly synthesized cephalosporins was evaluated by the minimum inhibitory concentration(MIC)against 30 Gram-positive and30 Gram-negative strains of bacteria.Four of the compounds showed good in vitro antibacterial activity,and we obtained two new lead compounds,XXTB-10 I and XXTB-10 P,by combining their antibacterial activity,antibacterial spectrum and synthesis difficulty.In the third chapter,the first synthesis of Cudraflavone C(1),Cudraflavone B(2),Cudraflavone A(3)and Artoheterophyllin D(4)was accomplished through a rational inverse synthesis analysis using 2,4,6-trihydroxyacetophenone and 2,4-dihydroxybenzoic acid as the raw materials after esterification,BK-VK rearrangement,nucleophilic reaction,Claisen rearrangement and olefin recombination reaction.The in vitro antibacterial activities of these four natural products were evaluated by MIC,and for the first time,Cudraflavone A(3)and Artoheterophyllin D(4)were found to exhibit significant antibacterial activities against Grampositive bacteria with MIC values ranging from 0.25 to 4 μg/mL.Chapter 4 provides an overview of the research work in this thesis and proposes further research directions.This thesis lays the foundation for further research on novel cephalosporins and natural isopentenyl flavonoids as antimicrobial agents,and provides new research ideas to alleviate the problem of multi-drug resistance.