Synthesis And Biological Studies Based On Quinazolinylpiperidine Carboxylic Acid Hydrazide Derivatives

Nitrogen-containing heterocyclic compounds are widely present in biologically active small molecules,which are important application prospects and research value in the creation of medicines and pesticides.However,as the main agents for controlling crop diseases,insects and weeds,agrochemicals play a pivotal role in the development of agricultural economic value-added.Quinazoline derivatives are a class of nitrogen-containing heterocyclic compounds with a broad spectrum of biological activities,which the synthesis and structural modification of these compounds have always been an important subject of organic and medicinal research.On the other hand,1,3,4-oxidazole/thiadiazole and 1,2,4-triazole compounds are five-membered nitrogen-containing heterocyclic compounds with unique biological activities,which have been generally concerned due to its excellent antibacterial,antiviral,insecticidal and anticancer activities.In this paper,the bioactive small molecule fragments were constructed in the same molecule based on the method of hybridization pharmacophores,the A,B,and C series of quinazoline compounds were designed and synthesized by using quinazolinylpiperidinyl hydrazide as raw material.In addition,we also tested the in vitro antibacterial and antifungal activities and preliminary analyzed the structure-activity relationship?SAR?.This work is summarized as follows:1.The series of quinazoline compounds A₁-A₂₆,B₁-B₅₁,and C₁-C₂₀ were designed and synthesized.The all target compounds were characterized by ¹H NMR,¹³C NMR,HRMS or IR and elemental analysis.Among these compounds,the structure of compounds A₄,B₉,B₅₀,and C₈ was further confirmed by single crystal X-ray diffraction analysis.2.The turbidimetric bioassay was conducted to evaluate in vitro antibacterial activities of target compounds against Xanthomonas oryzae pv.oryzae?Xoo?,Ralstonia solanacearum?Rs?,Xanthomonas axonopodis pv.citri?Xac?and Pseudomonas syringae pv.actinidiae?Psa?.The antibacterial tests indicated that compounds A₁,A₇,A₂₁,A₂₂,C₁,C₂,C₃,C₅,C₆,C₁₀,C₁₃,C₁₅,C₁₉,and C₂₀ exhibited excellent bioactivities against pathogenic bacterium Xoo,and its possess EC₅₀?half-maximal effective concentration?values of 30.4,30.6,27.5,26.0,28.6,30.2,23.6,28.0,18.8,23.4,27.1,27.9,28.5,and 24.3?g/m L,respectively,which were significantly superior to that of commercially available bactericide Bismerthiazol.Moreover,compounds A₂₁ and A₂₂showed good antibacterial activity against Xac with EC₅₀ values of 68.8 and 60.3?g/m L,respectively.In addition,the EC₅₀ values of compounds A₇,A₈,A₁₄,and A₂₁ against Rs were 50.8,36.5,50.2,and 39.4?g/m L,respectively.Among them,compound C₆ had the best activity against Xoo,with an EC₅₀ value of 18.8?g/m L,scanning electron microscope?SEM?imaging technique was used to find that the addition of compound C₆ resulted in partial folding or rupture of the pathogen cell membrane,which further confirmed that the designed compounds had strong destructive effect towards the rice bacterial leaf blight.3.The control efficiencies of compound C₆ against rice bacterial leaf blight were carried out under greenhouse conditions trials via the leaf-cutting method.The results showed that compound C₆ was effective in reducing rice bacterial leaf blight,with the protection and curative efficiencies of 56.23%and 52.30%,respectively,which were better than commercial control of Bismerthiazol?43.45%and 46.80%,respectively?and Thiodiazole-copper?45.34%and 42.43%,respectively?.4.Antifungal activities of target compounds against seven common fungi were assessed via mycelial growth rate method at the concentration of 50?g/m L,namely Gibberella zeae,Phytophthora infestans,Verticillium dahliae,Gloeosporium fructigenum,Cytospora mandshurica,Colletotrichum gloeosporioides,Sclerotinia sclerotiorum.The results indicated that some target compounds exhibited significant antifungal effects toward certain tests fungi.For example,compounds A₁,A₃,A₄,A₇,A₈,A₁₃,A₁₇,A₂₆,B₂,B₄,B₉,B₂₀,B₂₂,B₂₄,and B₄₈ against Gibberella zeae with the inhibition ratio of 55.7%,51.9%,61.6%,56.7%,56.2%,59.5%,56.5%,55.1%,57.8%,58.3%,51.9%,55.3%,62.8%,60.0%,and 53.7%,respectively,which were superior to commercially-available control Hymexazol?51.4%?.In addition,compound A₁ against Phytophthora infestans with the inhibition rate of 65.8%,the inhibition rates of compounds A₈,A₂₁,and A₂₆ against Verticillium dahliae were 76.4%,73.7%,and79.1%,respectively.The inhibition rate of compounds A₈ and A₂₂ against Colletotrichum gloeosporioide were 68.7%and 71.5%,and the inhibition rate of compounds B22 and B48 against Cytospora mandshurica were 71.2%and 64.1%.Notably,the compounds A₁,A₃,A₇,A₈,A₁₃,A₁₄,A₂₆,B₂,B₄,B₂₀,B₂₂,B₂₇,and B₄₈ demonstrated better and broad-spectrum fungicidal acitivties against the test types of phytopathogenic fungi.