Design,Synthesis And Bioactivity Of Tetronic Amine And Derivatives

Natural active substances are an important means to obtain lead compounds of pesticides.The five-membered heterocyclic skeleton compound Tetronic acid（Alternaria tenuiflora）has biological activities such as antibacterial,antiviral,weeding,and insecticide.In this paper,the active natural product tetronic acid（Alternaria tenuifonic acid）is fully synthesized,and a total of 28 tyrenic acid derivatives are designed and synthesized using the strategy of"natural product common pharmacophore-oriented".Their structures are confirmed by ¹H NMR,¹³C NMR,HR-MS,etc.The biological activity test results show that the target compound has certain bactericidal,insecticidal,weed-killing and anti-tumor biological activities,and there is a certain structure-activity relationship between structure and activity,indicating the value of tetronic acid as a lead compound for further research.In the future,more in-depth development of this kind of work will have laid a certain foundation.The specific content is as follows:1.Design and synthesis of Tetramic acids and its derivativesUsing Meldrum’s acid as the acyl acetylation reagent,the efficient synthesis of terine and the realization of different acylation substitutions at the 3-position are achieved,avoiding the use of highly toxic diketene reagents.2.Study on the activity of target compounds against plant pathogensThe activity results showed that at a concentration of 50 mg/L,the target compound had certain inhibitory activity against Fusarium oxysporum f.sp.Hiveum（E.F.Smith）Wollen.Colletotrichum orbiculare and Alternaria alternate（Fries）Keisslar spot disease.The inhibitory rate of the target compound 4d on Fusarium oxysporum f.sp.Hiveum（E.F.Smith）Wollen:37%,which is closer to the inhibitory rate of the positive control drug（azoxystrobin）of 52%and higher than the inhibitory rate of the natural active product Alternaria tenuiflora 4r which is 2%;The inhibitory rate of target compounds 4a,4f,4i,4k,4m,5a,5c,5d,7a against Alternaria alternate（Fries）Keisslar:22%～40%,which is close to or higher than the inhibition rate of the positive control drug（azoxystrobin）which rate is 60%and is higher than the inhibition rate of the natural active product Alternaria tenuiflora 4r which is 10%.3.Study on the herbicidal activity of the target compoundsThe activity results show that at a concentration of 100 mg/L,the target compounds have certain inhibitory activity on the germination of Portulaca oleracea and Amaranthus retroflexus seeds.The germination inhibition rate of the target compounds 4d,5b,5c,5e,5f,8a on Portulaca oleracea seeds:72%～96%which is higher than the positive control drug（atrazine）which is 69%and is higher than the germination inhibition rate of the natural active product Alternaria tenuifonic acid 4r which is 19%.The germination inhibition rate of the target compound 4d on Portulaca oleracea seeds is 96%,which is higher than the 69%germination inhibition rate of the positive control drug（2,4-D）.Among them,the EC₅₀ of the most active target compound 4d:0.189 mg/L.The germination inhibition rate of target compounds 4d,4h,5c,5e,and 5f on Amaranthus retroflexus seeds:70%～86%which is higher than the germination inhibition rate of its positive control drug（atrazine）which is 51%and higher than the germination inhibition rate of the natural active product Alternaria tenuifonic acid 4r:54%.The germination inhibition rate of the target compound 4d on Amaranthus retroflexus seeds was 86%,which was higher than the 79%germination inhibition rate of the positive control drug（2,4-D）.Among them,the EC₅₀of the most active target compound 4d:0.168 mg/L.4.Study on the insecticidal activity of target compoundsThe activity results show that when the concentration is 100 mg/L,the target compounds all exhibit certain insecticidal activity.When the time reaches 24 hours,the corrected mortality of the target compound 4s,5a,5b,5d,5e,5f,5g against Macrosiphum avenae（Fabricius）is 43%～82%,which is higher than the corrected mortality of the positive control drug（Spirotetramat）which is 40%;when the time reaches 48 hours,the corrected mortality of target compounds 5c,5d,5e,7a,8a against Macrosiphum avenae（Fabricius）is 93%～100%,which is higher than the corrected mortality of the positive control drug（Spirotetramat）which is 89%;when the time reaches 72 hours,except for the target compounds 4a and 4g have corrected mortality rates of 50%and 57%,respectively,the corrected mortality rates of the remaining target compounds are all higher than 70%.Until 96 hours,except for 4a,4g have corrected mortality rate of 4g was 80%and 68%,respectively,and the corrected mortality rate of the other target compounds reach 100%.The corrected mortality rates of the target compounds 4d,5c,and 5e are 41%,94%,and 97%,respectively.When the 5th position is fixed as n-butyl,the 3rd position substituent can be modified to increase the death of the tube aphid rate.The natural active product Alternaria tenuifonic acid 4r has a corrected mortality rate of 48%against wheat after 24 hours,86%after 48 hours,97%after 72 hours,and reach to 100%after 96 hours.After 24 hours,the corrected mortality of the target compounds5b,5d,5f,and 5g are 54%to 83%,which is higher than 4r;after 48 hours,the target compounds 5a,5c,5d,5e,7a,8a have the corrected mortality rate 88%to 100%,which is higher than 4r.It can be seen that our targeted modification of positions 3,4,and 5 can improve the mortality of Macrosiphum avenae（Fabricius）.These data show that the target compounds we designed and synthesized have higher activity against Rhopalosiphum avenae and show that these target compounds have potential research significance and value when used as insecticides.5.Study on the medicinal activity of the target compoundThe activity results show that the target compounds 4c,4d,4f,4i,4k,4o,4p,5b all have good drug sensitivity to A549 cell line（adenocarcinoma human alveolar basal epithelial cells）,and their IC50 is 0.528mg/L,0.591 mg/L,0.506 mg/L,0.882 mg/L,0.866 mg/L,0.78 1mg/L,0.849 mg/L,0.682 mg/L.For the H1299 cell line（human lung cancer cells）,the target compounds 4c,4d,4f,4i,4j,4m also have good constant activity,and their IC50 is 1.432 mg/L,1.225 mg/L,and 1.11 mg/L,respectively.L,1.951 mg/L,1.99 mg/L,1.972 mg/L.CHL cell line（hamster lung cells）did not find any more active target compounds.