Synthesis And Bioactivity Of Carbazolyl Isopropanolamine Derivatives

Carbazole derivatives play an extremely important role in the field of medical research due to their broad spectrum of bioactivity.Based on the previous studies on the biological activities of carbazole compounds in our research group,a series of carbazole-based isopropanolamine compounds have been designed and synthesized with isopropanol as the link chain by used substructural active splicing method,which were characterized by ¹H nuclear magnetic resonance（¹H NMR）,¹³C nuclear magnetic resonance(¹³C NMR),and high resolution mass spectrum（HRMS）.Their in vitro antibacterial activities against Xanthomonas oryzae pv.oryzae（Xoo）,Xanthomonas axonopodis pv.citri（Xac）,and Pseudomonas syingae pv.actinidiae（PSA）respectively,were evaluated by the turbidimeter test.The greenhouse trials and mechanism of action of the target compounds with excellent bioactivity were also performed.3,6-position substituted carbazole as the starting material,through the substitution reaction of epoxy propane and carbazole nitrogen atoms are linked together,using different substituted amino ring-opening reaction,synthesis of 37 new structure of 1-（substituted amino）-3-（3,6-substituents-9H-carbazole-9-yl）-2-propanol compounds I.Biological activity test results showed that the EC50 of compounds I₁-I₂₀ and I₂₅-I₃₇ against Xoo was within the range of 0.902³5.4μg/mL,which was more better than that of control agents BT and TC（92.61 and 121.82μg/mL）.Compounds I₁-I₂₀,I₂₇-I₃₇,and the EC50 of Xac in the range of 0.993³0.5μg/mL also far exceeded the control agent TC inhibitory activity（77.04μg/mL）.The EC50 of compounds I₁-I₇,I₉-I₁₂,I₁₄-I₁₇,I₁₉,I₂₀ and I₂₄ against PSA ranged from 0.603³2.0μg/mL,and their inhibitory activities were also significantly higher than those of the control agents BT and TC（111.2 and 87.0μg/mL,respectively）.Meanwhile,the control efficiencies of compound I₁₅ against rice bacterial leaf blight were carried out under greenhouse conditions via the leaf-cutting method and the results indicated that compound I₁₅ was effective in reducing rice bacterial leaf blight,with the curative and protection efficiencies of 50.77%and48.71%,respectively,relative to an untreated control as well as the commercial bactericides of BT（43.47%and 40.91%）and TC（42.60%and39.17%）.In order to further improve the biological activity of the target compound,on the basis of route 1 target compound I₃₇,15 1-(（1-substituted group-1H-1,2,3-triazole-4-yl）methyl（amino）-3-（9H-carbazole-9-yl）-2-propanol compounds II were synthesized by click chemical reaction.Biological activity test results showed that the EC50 of compounds II₁-II₉ and II₁₁-II₁₅ on Xoo was within the range of 3.36⁸.28μg/mL,which was far lower than the control agents BT and TC.The EC50 of compounds II₁-II₉ and II₁₁-II₁₅ on Xac ranged from 2.87¹2.9μg/mL,which also far exceeded the inhibitory activity of the control agent TC.Scanning electron microscope（SEM）imaging technique was used to find that the addition of compound I₁₅ resulted in partial folding or rupture of the pathogen cell membrane;At the same time,the results of fluorescence titration showed that compound I₁₅ had a strong interaction with the DNA of Xoo.In order to further explore the mechanism of action,proteomics technology was used to analyze the compound I₁₅ processing of Xoo of protein expression changes in the experimental group and the control group,the results showed that there were significant changes of 247 proteins.Particularly,theBeta-glucosidase,Fructokinase,Endoglucanase,Trehalose-6-phosphate synthase and Trehalose 6-phosphate phosphatase significant changes of starch and sucrose metabolism pathways.Significant changesinMalonyl-（acyl-carrierprotein）-O-methyltransferase,Beta-ketoacyl-synthase I and 3-oxoacyl-（Acyl-carrier-protein）reductase affect the synthesis of fatty acid,resulting in abnormal biotin metabolism.The parallel reaction monitoring（PRM）technique was used to verify the differential expression proteins,it was afforded the same trends with the label-free quantitative proteomics data.Therefore,we speculated that the target compound I₁₅ may affect the energy metabolism process of bacteria,resulting in the bacteria’s inability to carry out material transportation,and then inhibit the cellular respiration to result in the death of bacteria.