Synthesis And Bioactivity Determination Of Picrotoxinin Simplified Analogues

Picrotoxinin is a sesquiterpene lactone natural product isolated from the plant Menipermum cocculus.It is a non-competitive antagonists of GABA receptor and have potential insecticidal activity.In order to explore its application in plant derived pesticides,a series of simplified analogizes were designed and synthesized based on the bicyclic skeleton[6-5]as core structure.The insecticidal effects on the early third stage armyworm were determined.In addition,the inhibitory activities on plant pathogenic fungi were explored,and the results were as follows:（1）A total of 32 compounds were synthesized,including 5 intermediates and 27analogies.These compounds including 14 halogen-containing compounds and 13halogen-free compounds,all of which are new compounds.Their structures were confirmed by ¹H NMR,¹³C NMR and optical rotation,and the absolute configuration of compound 8 was determited by X-ray single crystal diffraction.（2）The oral toxicity of the target compound against the third-instar larvae of M.separate.at the concentration of 1 mg/m L was determined by leaf dipping method,and it was found that compound 2-17b has certain insecticidal activity.（3）The activities of these 27 compounds against four plant pathogenic fungi were determined by the mycelial linear growth rate method at the concentration of 50μg/m L.In the experiment of antifungal activity against plant pathogenic fungi,the antifungal agent kresoxim-methyl（KM）was used as a positive control.The preliminary results showed that among the 27 simplified analogs,6 compounds showed certain bacteriostatic activity against the tested bacteria.Among them,compounds 2-17g and 2-17h showed good antibacterial activity against four pathogens,such as Fusarium oxysporium sp.vasinfectum,Fusarium graminearum,Alternaria solani and Valsa mali,while compound 2-17j showed good antibacterial activity to the positive control kresoxim-methyl against three pathogens except Fusarium graminearum.In conclusion,the[6,5]bicyclic skeleton of picrotoxinin was constructed by 7-step procedure with 11.7%overall yield.From this key intermediate,novel simplified analogues were designed and synthesized.Through activity evaluation,it was found that the introduction of chlorine-containing benzene ring structure into the hydroxyl site of the six-member ring of parent nuclear structure could improve the antibacterial activity of the target compound.These results provide some experimental data support for the structural modification and antibacterial activity of these compounds in the future.