Synthesis,Antifungal Activity Of Drimane Meroterpenoids And Analogues

As important resources for the creation of new pesticides,natural products have been playing a significant role in the pharmaceutical and agrochemical industry.Drimane-related meroterpenoids and analogues have drawn considerable attention,with the abundance of distribution,structural diversity,and various biological properties ranging from anti-fungal to anti-tumor and anti-inflammatory,etc.The exporations of drimane-related meroterpenoids natural products were mainly concentrated in the medicinal industry,while the structure optimization and structure-activity relationship with the goal of creating new agrochemicals were limited.Herein,a series of drimane-related meroterpenoids and analogues were synthesized using inexpensive and readily available sclareol and sclarelide.Antifungal exploration and SAR study for the discovery of new agrochemicals of the target compounds were carried out.The results were as follows,(1)Synthesis of the ?,?-unsaturated ketone mimics was accomplished through the nucleophilic attack to sclareolide by lithium methide,and followed by the aldol condensation with easily available and inexpensivebenzaldehydes.A wide variety of heterocycles,including isoxazoline,isoxazole,pyrimidine and pyrazole,were synthesized efficiently based on the ?,?-unsaturated ketone mimics..A total of 59 Drimane-related meroterpenoids analogues were synthesized.The target compomounds were confirmed by Electrospray Ionization Mass Spectrometer(ESI-Mass),1H-Nuclear Magnetic Resonance(1H-NMR)Spectroscopy,13C-Nuclear Magnetic Resonance(13C-NMR)Spectroscopy,Distortionless Enhancement by Polarization Transfer 135(DEPT135)and X-ray crystallography.The antifungal activities against a number of agriculturally important plant pathogens,including Rhizoctonia solani,,Sclerotinia scleotiorum,Fusarium graminearum,Botrytis cinerea,Phytophthora capsici,Gaeumanomyce graminis,Colletotrichum lagenarium,Fusarium sulphureum,Fusarium fuJikuroi,Alternaria solani,were measured through the mycelium growth rate test.The results indicate that the compounds possess moderate to excellent antifungal bioactivity against all the test fungi.Compound 3a,3c and 2z have good antifungal activity and can be used as potent fungicidal leads.The EC50 values of compound 3a and 3c against B.cinerea were as low as 3.22 mg/L and 5.90 mg/L,with>40 folds and>20 folds more promising than carbendazim(146.56 mg/L),respectively.The preventative efficacy of compound 3a and 3c against B.cinerea was carried out.The preventative efficacy of compound 3a and 3c under 200 mg/L,was 38.24%and 26.66%,respectively which was more powerful than that of the positive control carbendazim(23.39%).(2)Barton decarboxylation coupling was explored and established.The synthesis of drimane-related meroterpenoids natural products and analogues was accomplished with sclareol as starting materials.The preparation of(+)-yahazunol and drimane-related meroterpenoids natural products(+)-chromazonarol,(-)-zonarone,(-)-zonarol,(-)-isozonarol,(-)-isozonarone and(+)-yahazunone and analogues was accomplished.The antifungal activities of these natural products and analogues against seven important plant pathogens,including R.solani,S.scleotiorum,F.graminearum,B.cinerea,P.capsici,G.graminis and Magnaporthe oryzae,were measured.The results demonstrated that the natural compounds(+)-chromazonarol and(+)-yahazunone possessed promising antifungal bioactivity against S.scleotiorum,with the EC50 values of 7.57 and 9.47 mg/L,respectively.(+)-Yahazunol and related natural products can serve as novel fungicidal leads for further optimization and modification,which will lay asolid foundation for the discovery of novel agrochemicals with drimane-related meroterpenoids natural products.In summary,drimane-related meroterpenoids natural products were designed and synthesized with inexpensive and readily available natural products with sclareol and sclareolide as starting materials.(+)-Yahazunol and 6 related natural products were synthesized,and 74 drimane meroterpenoids mimics were synthesized..The antifungal activity and structure-activity relationship study of all the target compounds were conducted.Compound 3a,3c,and(+)-chromazonarol were protruded as antifungal candidates,which laid a solid foundation for the discovery of novel antifungal agrochemicals based on drimane-related meroterpenoids.