Synthesis And Bioactivities Of Novel 3-phenyl-4-hydroxypyrroline-2-one Derivatives

The 4-hydroxypyrrolidin-2-one（terephthalic acid）skeleton compound shows biological activities such as anti-phytopathogenic bacteria,insecticide,acaricide and herbicide,and is widely found in natural products,commercial pharmaceuticals and pesticides.In this paper,30 novel 3-phenyl-4-hydroxypyrrolidin-2-one derivatives were designed and synthesized using a co-active pharmacophore strategy with natural active product Te A as the lead compound.The target compounds were also structurally characterized by ¹H NMR,¹³C NMR,DEPT,HSQC and HRMS.The results of biological activity assay demonstrated that some of the target compounds had high insecticidal and acaricidal and herbicidal activities and had a structure-activity relationship.The findings of such research have some implications for future in-depth studies.The details of the study are as follows.1.Synthesis of novel 3-phenyl-4-hydroxypyrrolidin-2-one derivativesUsing natural active product Te A as the lead compound,the efficient synthesis of 30 novel3-phenyl-4-hydroxypyrroline-2-one derivatives was completed and the polyfunction of the5-position in the structure was realized.2.Determination of antifungal activity and structure-activity relationshipThe target compounds had no significant inhibitory effect on Fusarium graminearum,Pellicularia sassakii and Erysiphe cucurbitacearum,and the inhibition rate did not exceed50.00%at the concentration of 50 mg/L.The structure-activity relationship indicates that the inhibitory activity of the compounds against Pellicularia sassakii increases with the increase in the spatial structure of the substituent at the 5-position in the structure.After the introduction of ester group at the 4-position,the inhibitory activity against Fusarium graminearum was improved distinctly.3.Determination of insecticidal and acaricidal activity and structure-activity relationship（1）The target compounds showed vital insecticidal activity against Aphis craccivora.The determination of combined method（stem aspiration and leaf-bearing leacher）showed that corrected mortality rates were 100%for the target compounds 4f,4g,4l,4o,4q and 4r at the concentration of 500 mg/L.Among them,4l and 4r at the concentration of 50 mg/L were still 100%and 96.96%,and imidacloprid was 100%.The determination of leaching method showed that the corrected mortality rates of 4f and 4r at the concentration of 50 mg/L were97.92%and 100%respectively,and imidacloprid was 100%.（2）The target compounds showed high acaricidal activity against Tetranychus cinnabarinus.The determination of combined method showed that the corrected mortality of target compounds 4f and 5g at 500 mg/L concentration were 94.59%and 80.98%,respectively,of which 5g was still 83.33%at the concentration of 50 mg/L.The determination of leaching method showed the corrected mortality rate of 98.41%for 5g at the concentration of 50 mg/L and 82.33%for 5d at the concentration of 10 mg/L,higher than that of spinosad（81.81%）.（3）The structure-activity relationship showed that when the 5-position of the target compound was fixed as a spiro ring and the 3-position was 2,4-dichlorophenyl,it had higher activity against Aphis craccivora and Tetranychus cinnabarinus.And the insecticidal activity against Aphis craccivora increased with the increase of the spatial structure of the substituent at the 5-position.And the insecticidal activity against Aphis craccivora increased with the increase of the spatial structure of the substituent at the 5-position,but when the 3-position was 2,5-dimethylphenyl,the activity against Tetranychus cinnabarinus disappeared.After the introduction of ester group at the 4-position,the acaricidal activity against Tetranychus cinnabarinus was significantly improved,but the insecticidal activity against Aphis craccivora disappeared.4.Determination of herbicidal activity and structure-activity relationship（1）The target compounds had significant inhibitory activity against the seed germination of Portulaca oleracea and Echinochloa crusgalli:at the concentration of 100 mg/L,the germination inhibition rates of 4e,4i and 5d on the seeds of Portulaca oleracea were 81.05%,80.16%and 80.04%,respectively,higher than that of atrazine（54.50%）and natural product Te A（32.44%）,and the germination inhibition rates of Echinochloa crusgalli were 91.03%,92.74%,and 90.19%,respectively,and the metolachlor was 90.85%,higher than that of atrazine（57.76%）and Te A（35.34%）.Among them,the EC₅₀ value of the germination inhibition rate of 4e on the seeds of Portulaca oleracea was 1.956 mg/L,and the value of Echinochloa crusgalli was 1.748 mg/L.（2）The indoor potted weed control determination showed that the target compounds were more active in weeding Echinochloa crusgalli and Portulaca oleracea,but weaker on Brassica napus and Amaranthus tricolor.At the effective administration dose of 100 g/hm²,the fresh weight inhibition rates of 4b,4d and 4o on Echinochloa crusgalli were 93.33%,91.27%and 92.18%,respectively,much higher than that of Te A（1.86%）.The fresh weight inhibition rates of 4b,4c,4d,4o,4q and 4r on Portulaca oleracea were 100%,and the fresh weight inhibition rates of mesotrione were 100%,higher than that Te A（0.71%）;The fresh weight inhibition rates of 4d and 4r on Brassica napus and Amaranthus tricolor were 57.22%and 64.21%,respectively.（3）The structure-activity relationship indicated that the seed germination inhibitory activity of the target compound was enhanced with the increase of the steric structure of the5-position substituent.And when the 3-position of the structure is 2,4-dichlorophenyl and2,5-dimethylphenyl,respectively,the herbicidal activity of the former is higher than the latter.When the ester group was introduced at the 4-position,the inhibitory activity of seed germination was enhanced to varying degrees.The herbicidal activity of indoor pot was stronger when 3-position was 2,4-dichlorophenyl,and 5-position was methyl,ethyl,isopropyl,cyclopropyl,cyclopentyl and cyclohexyl,but there was no obvious activity when3-position was 2,5-dimethyl phenyl,and the activity disappeared when 4-position was introduced into ester group.5.Discussion on the mechanism of seed germination inhibition of target compoundsMechanism of herbicidal action of target compound 4e was studied by using wild-type Arabidopsis thaliana seeds.The results showed that with the increase of the concentration of target compound 4e in MS medium,the content of endogenous hormone ABA increased and the relative expression levels of ABI1 and ABI2 genes decreased while ABI5 gradually increased.And the germination rate of seeds after the addition of Na₂WO₄（ABA inhibitor）was significantly improved compared with the previous.The results above preliminarily proved that the target compound 4e affected the germination of seeds by regulating the content of ABA in seeds.