Study On The Mechanism And Antibacterial Activity Of Vinyl Aromatic-substituted Quinoline Derivatives As FtsZ Inhibitors

Nowadays,the emergence of bacterial infection diseases has always been one of the important threats to human health and safety.With the abuse of antibiotics,Drug-resistant bacterial infections are becoming more serious.Therefore,finding new targets and new antibacterial agents is the important target of many pharmacologists.Filamentous temperature-sensitive protein Z(FtsZ)is considered as an ideal target for the development of new antimicrobial agents due to its high conservatism and importance.Recent studies have shown that the modification of quinoline derivatives plays an active role in antibacterial activities,and has certain inhibitory effects on the polymerization of FtsZ and the activity of GTPase.Our research group have designed and synthesized a series of vinyl aromatic-substituted quinoline derivatives in the early stage,and in this thesis,the antibacterial activity of these derivatives and the mechanism of their interaction with FtsZ were studied.The main contents of this thesis include:(Ι)In the study of antibacterial activity: 1.In vitro antibacterial activity tests,we found that the antibacterial effect of vinyl aromatic-substituted quinoline derivatives against gram-positive bacteria was better than that of gram-negative bacteria.The MIC values of some compounds against MRSA and VRE could be reached 1-4 μg/mL,and the introduction of piperidine,pyrrolidine and indoles had positive antibacterial effect.2.In the study of bacterial morphology,compounds a4,a12,a13 and a19,with good antibacterial effect,inhibit bacterial division on the basis of not damaging bacterial cell membrane structure,resulting in blocked bacterial division and continuous extension to 50-140 μm,and eventually bacterial death.3.The compounds have a positive synergistic effect with methicillin,and effectively reduce the frequency of drug resistance.4.Vinyl aromatic-substituted quinoline derivatives are generally cytotoxic.(Ⅱ)In the study of mechanism of action against FtsZ: 1.In the enzyme activity tests,a4,a12 and a13 showed an inhibitory effect,which was different from the promoting effect of a19.Both a4 and a19 strongly disrupt the polymerization of FtsZ in a dose-dependent manner.2.The compounds can not only inhibit bacterial division,but also effectively interfere with the normal formation of Z-ring.3.In molecular docking study,the compounds can interact with the amino acid residue of FtsZ protein through the interaction of Carbon-hydrogen bonds,Pi-Sigma and Pi-anions.This may have a significant effect on improving the antimicrobial activity of the compounds.The results of this thesis showed that vinyl aromatic-substituted quinoline derivatives have certain advantages in the development of antibacterial drugs,especially the introduction of piperidine,pyrrolidine and indole groups have a significant impact on the improvement of antibacterial activity.In addition,it has certain promoting effects on both resistance to bacteria and combination with methicillin.Moreover,the series of compounds can disrupt the polymerization of FtsZ protein and the formation of Z-ring by affecting the enzyme activity.However,the cytotoxicity of these compounds needs to be further reduced.