Design And Synthesis And Structure-Antimicrobial Activity Relationship Of Acinetobactin Analogues

Oxazoline and its bio-isostere thiazoline skeleton are widely found in many drugs and natural products,such as:Acinetobactin,Anguibactin,Bacillamide,etoxazole,etc.Based on the aryl oxazoline pharmacophore discovered by the research group in the early stage and the natural product Acinetobactin,a new type of oxazoline amide,hydrazide and other analogs were designed and synthesized in this paper,and its antifungal,antibacterial and complexing activity with metal ions was measured,based on the structure-activity relationship study,a number of novel arylthiazolinamide（hydrazine）fungicides lead compounds have been discovered,and the results are as follows:（1）Based on the natural product Acinetobactin,using cheap and easily available benzoic acid,benzaldehyde,benzonitrile,benzamide and aniline compounds,designed and synthesized arylthiazoline amide,aryloxazoline amide,arylthiazole 5 kinds of aryl heterocyclic amides,including amide,aryl isoxazoline amide,aryl isoxazoline amide,and a total of 60 compounds;based on the structure-activity relationship,15 new aryl thiazoline hydrazide molecules were synthesized With 5 aryl heterocyclic-heterocyclic analogs,and verified by ¹H-NMR,¹³C-NMR,and ESI-HRMS,etc.The structural correctness of the target compound is verified.（2）The antifungal activity of the prepared aryl heterocyclic amide and hydrazide compounds was tested,and the growth rate inhibition method was used to determine the resistance to R.s and S.s,F.g,P.c,B.c and G.g,inhibition of 6 common plant pathogens.The antifungal activity assay found that the EC50 values of compounds B2,B3,B4,B5,B9,B10,B11,B12,B13,and B14 against R.s were all lower than those of the positive control Pydiflumetofen.The EC50 can be as low as 0.13μg/m L;the EC50 of compounds B2,B5,B9,B10,B11,A16,and A56 for S.s are lower than the positive control Pydiflumetofen,and the EC50 of compound B2 can be as low as 0.18μg/m L.Through structure-activity relationship studies,the antifungal activity of thiazoline hydrazide molecules is better than that of thiazoline amide molecules and bi-heterocyclic molecules;when the aryl group of the hydrazine part of the thiazoline hydrazide molecule is introduced with a single-substituted fluorine atom,the corresponding thiazoline The hydrazide compound has the best activity（B2,B11）,and can be used as a lead compound for fungicides.（3）The antibacterial activity of the prepared aryl heterocyclic amide and hydrazide compound was determined,and the MTT assay method was used to determine the antibacterial activity.The antibacterial activity of the prepared aryl heterocyclic amide and hydrazide compound was tested against Ralstonia solanacearum,Bacillus subtilis,Pectobacterium carotovorum subsp.Carotovorum,Pseudomonas syringae pv.Lachrymans,Xanthomonas oryzae pv.oryzicola,Xoc,Lavibacter michiganense.It was found that only the B series of compounds had an inhibitory effect on Xoc.Compounds B1,B2,B3,B4 and B6had the same MIC for Xoc as the positive control streptomycin sulfate,both of which were 4ppm.The MIC of compound B5 to Xoc is better than streptomycin sulfate and can reach 2ppm.The iron ion complexing activity test results show that B2,B3,B5,B6 all have iron ion complexing activity,compound B5 still has complexing activity at 0.125ppm,the iron ion complexing activity test result and the antibacterial activity test result show A certain relevance,which provides us with ideas for the follow-up study of its antibacterial mechanism.（4）It was found that in the process of synthesizing arylthiazoline amide（hydrazine）,the product has a certain degree of racemization,and its enantioselectivity is affected by the type of condensing agent and base;by controlling the solvent,condensing agent and base in the condensation process A highly selective condensation method was established（HATU was used as a condensing agent,no alkali was added,and dichloromethane was used as a solvent）,which increased the enantioselectivity of the target compound to 73%ee.The antifungal activity test results show that the compound’s antifungal activity is significantly related to the configuration of the compound.It is speculated that the L-configuration condensation product is more beneficial to the antibacterial activity.For example,at a concentration of 50 mg/L,the ee of compound A56 When the value is reduced from 73%to51%,the inhibition rate of Rapeseed Sclerotium is reduced from 90%to 51%.In this paper,based on the natural product Acinetobactin,three types of 80 new heterocyclic amide（hydrazine）compounds were designed and synthesized,and the antimicrobial structure-activity relationship was studied.Compounds B2,B3,B4,B5,B11,B12 were screened out,which can be used as control lead compounds of agricultural fungicides for R.s,B2,B5,B9,B10,B11,A16,A56 can be used as lead compounds for agricultural fungicides for the prevention and treatment of S.s,B2,B3,B4,B5,B6,B7 as a leading compound of agricultural fungicides for the prevention and treatment of Xoc;established a highly selective method for the synthesis of thiazolinamides,providing new construction methods and new structural optimization directions for the creation of new amide（hydrazine）fungicides.