Synthesis And Antibacterial Activity Of Amide Derivatives Containing Reactive Groups

Cysteine is a covalent amino acid residue with an electron-rich sulfhydryl group in its side chain,which reacts with electrophilic groups in drug molecules to form stable covalent bonds through addition,substitution and oxidation.Simultaneously,acrylamide is a reactive group of cysteine sulfhydryl,has been successfully introduced into anticancer and anti-tumor drug molecular design in recent years,and some drugs have been commercialized.Meanwhile,derivatives containing quinazoline have a wide range of biological activities,such as anti-cancer,antibacterial,anti-viral and anti-inflammatory,and so on.Moreover,furan ring derivatives have been attracting attention due to their excellent antibacterial activity.Two aspects were mainly studied in this thesis.The first one is synthesis and biological activity research the quinazoline compounds containing acrylamide groups,the second is antibacterial activity of quinazoline derivatives containing furan structure and the preliminary exploration of the mechanism of action.1.We used the quinazoline with different substituents as scaffolds,the acrylamide group and alkynyl group are introduced at the 4-position were synthesized and characterized by ¹HNMR,¹³CNMR and HRMS.The biological activities of all the title compounds against Xanthomonas oryzae pv.oryzae(Xoo),X.axonopodis pv.citri(Xac)were examined using the turbidimeter test in vitro.The results showed that the series showed good bioactivity to the compound against Xoo and Xac.Further studied suggested that the compounds A₁,B₄ and C₄with EC₅₀ value 3.67?2.01 and 6.24?g/mL,respectively.Which better than the control agent Bismerthiazol(EC₅₀ value was 92.6?g/mL).Besides,for against Xoo,some compounds have better inhibition effects activity,the EC₅₀ values of most of the compounds were ranging from 6.85 to 65.0?g/mL,which slightly lower than the control agent Thiodiazole copper(EC₅₀ value was 77.0?g/mL).2.A total of 33 quinazoline derivatives containing furan structure were designed and synthesized,characterized by ¹H NMR,¹³C NMR,¹⁹F NMR and HRMS.All of the target compounds were tested for inhibition activity against the phytopathogenic bacteria Xoo and Xac under in vitro.The results showed that the series compounds showed good biological activity against Xoo and Xac,compounds E₂and F₁ with EC₅₀value 7.03 and 7.13?g/mL,respectively.Meanwhile,the compounds H₄ showed good bioactivity toward Xac,EC₅₀ value was 10.4?g/mL,better than of Thiodiazole copper(EC₅₀ value was 77.0?g/mL).In addition,we studied compounds E₂and F₁ against Xoo control effect in vivo.Experimental results show,in concentration of 200?g/mL,the curative activity of E₂ and F₁ were 51.5%and 49.0%,respectively,which were superior to the control agents Bismerthiazol(39.9%)and Thiodiazole copper(41.6%).At the same time,the protective activity of E₂ and F₁ were 49.8%and 52.1%,respectively,which were better than the control agents Bismerthiazol(40.2%)and Thiodiazole copper(39.2%).Besides,we observed the changes in cell morphology caused by the interaction of compounds F₁ and H₄ with Xoo and Xac,respectively,by scanning electron microscopy,The results showed that the morphology of plant pathogenic bacteria was damaged and crumpled at the concentrations of 50 and 100?g/mL,respectively.Finally,we explored the possible mechanism of the action of compound F₁ on Xoo is used label-free quantitative proteomics.Results indicate that compound F₁could dramatically induce the up-regulation and down-regulation of an array of expressed proteins which probably involved in two metabolic pathways including starch and sucrose metabolism pathway and biotin metabolism pathway,thereby affecting bacterial energy metabolism and further causing bacterial death.