Synthesis And Agriculturalactivities Of Piperine-based Derivatives And Ester Derivatives Of (2α),2’(2’,6’)-Halogenopodophyllotoxins

Part I:Piperine,a naturally occurring cinnamamide alkaloid,has a variety of biological activities such as antitumor,antioxidant,neuroprotective effects and antimicrobial activities.Moreover,piperine and its derivatives are toxic to many agricultural pests such as Mythimna separata Walker.We prepared two series of 72 piperine-based derivatives including 66 new compounds on the basis of previous studies.Meanwhile,we also investigated their insecticidal activity/narcotic activity against the larvae of M.separata,stomach toxicity against Plutella xylostella Linnaeus and contact toxicity against the female adults of Tetranychus cinnabarinus Boisduval.The structure-activity relationships（SARs）were analyzed.The key results were as follows:（1）A series of 41 piperine-based phenylsulfonylhydrazone derivatives including 35novel compounds were designed and synthesized by changing of the dioxymethylene ring fragment,lengthening/shortening of olefin chain,and introduction of different phenylsulfonyl groups.Among all derivatives,especially the compound I-16s exhibited potent insecticidal activity against the larvae of M.separata with the final mortality rate（FMR）of 79.3%at 1mg/m L.The compound I-16p showed pronounced narcotic activity against the larvae of M.separata(ND₅₀:0.88μmol/g).The compounds I-16o and I-17f displayed excellent stomach toxicities against the larvae of P.xylostella treated at 20μg/larva with the FMRs of 82.8%and 89.7%after 48h,respectively.At 1 mg/m L,compounds I-16d、I-16j、I-16k and I-16l exhibited potent acaricidal activitives against the female adults of T.cinnabarinus with the FMRs of 52.7%,53.6%,55.9%and 51.9%after 72h,respectively.The SARs were as follows:1)the dioxymethylene ring fragment was important to insecticidal and narcotic activities against M.separata;2)olefin chain with two C=C bonds was essential to narcotic activity and stomach toxicity;3)lengthening of olefin chain with three C=C bonds was favorable to insecticidal activity against M.separata,while shortening of olefin chain with one C=C bond was favorable to contact toxicity against T.cinnabarinus.（2）A series of 31 piperine-based pyrazoline/isoxazoline derivatives were designed and synthesized by structural modification of piperine.The compound II-8c exhibited potent insecticidal activity against the larvae of M.separata with the FMR of 65.5%at 1 mg/m L;at20μg/larva,the compound II-8b displayed excellent stomach toxicity against the larvae of P.xylostella with the FMR of 72.4%after 48h;the compound II-8e displayed promising contact toxicity against the female adults of T.cinnabarinus(72h at LC₅₀:0.39 mg/m L).The SARs suggested that:1)for piperine-based pyrazoline derivatives,dioxymethylene ring fragment was important to insecticidal/acaricidal activities.Meanwhile,introduction of fluorine atom or chlorine atom on phenyl of pyrazoline ring could contribute to improve the insecticidal/acaricidal activities;2)dioxyethyl ring was important to contact toxicity against T.cinnabarinus for piperine-based isoxazoline derivatives.Part II:Podophyllotoxin and its derivatives showed a variety of biological activities,such as antitumor,antiviral,insecticidal,hypolipidemic,antirheumatic activities and so on.In recent years,we have carried out a study of podophyllotoxin derivatives and found that some derivatives exhibited more promising insecticidal activities than toosendanin.Herein,two series of 56 new podophyllotoxin derivatives were prepared and evaluated for their insecticidal activity against the larvae of M.separata/contact toxicity against the female adults of T.cinnabarinu.The SARs were analyzed.The main results were as follows:（1）Thirty-five ester derivatives of isoxazoline/isoxazole-containing podophyllotoxin/2′（2′,6′）-（di）halogenopodophyllotoxin were prepared by modification on the E ring and then at the C-4 position of podophyllotoxin by 1,3-dipolar cycloaddition.The compound III-21m exhibited good insecticidal activity against the larvae of M.separata at1mg/m L with the FMR of 72.4%;the compound III-22h and III-22m showed promising acaricidal activitives against the female adults of T.cinnabarinus at 0.5 mg/m L with the FMRs of 41.1%and 38.0%,respectively.It demonstrated that introduction of chlorine atom at the C-4 position on the phenyl of their isoxazoline/isoxazole fragment was favorable to the insecticidal and acaricidal activities.（2）By modification on the E ring,and at the C-2 and C-4 positions of podophyllotoxin,a series of 21 ester derivatives of 2α-bromo-2′（2′,6′）-halogenopodophyllotoxin derivatives were then obtained.All the target derivatives displayed more potent acaricidal activities against the female adults of T.cinnabarinus than podophyllotoxin at 0.5 mg/m L,especially the compound IV-7h(LC₅₀at 72h:0.59 mg/m L)and IV-7l(LC₅₀at 72h:0.60 mg/m L).The introduction of acetoxy moiety or benzyl acetoxy at C-4 position of podophyllotoxin was beneficial to improving acaricidal activity.In conclusion,four series of 128 piperine and podophyllotoxin derivatives including 122new compounds were prepared.Their agricultural activities against agricultural pests such as M.separata,P.xylostella and T.cinnabarinus were evaluated and the SARs were also observed.The above-mentioned results will pave the way for further research and development of piperine and podophyllotoxin derivatives as botanical pesticides.