Synthesis,Structure Optimization And Bioactivity Of Natural Sesquiterpenoid Drimenal

Drimane sesquiterpenoids are associated with a widespread spectrum of biological activities,including antitumor activity,antifungal,antibacterial and anti-HIV activities.Additionally,properties including plant-growth regulation,insecticidal activity and antifeedant activity are also widely reported.Drimane sesquiterpenoids also play key roles in food additives and perfume industry.Recently,the exporations of drimanes were mainly focused on medicinal and pharmaceutical chemistry,while the investigation in agrochemical only received attention limited seriously.The separation of drimenal,a natural sesquiterpenoid with significant antioomycetes activities,drawn our interest in the synthesis and aptimization of drimane analogues.Herein,commercially inexpensive available(-)-sclareol,was used as a starting material for the preparation of drimenal.Researches on optimization.Designing structure and biological activities of drimane analogues were also carried out.The results were as follows:(1)The synthesis of drimenal and drimenol were finished through oxidative degradation,nucleophilic ring opening,Baeyer-Villiger rearrangment reactions with(-)-sclareol as a starting material.The structures were determined based on LC-MS,1H-NMR,13C-NMR and DEPT 135.The fungicidal activities of the drimenol and drimenal against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum,Botrytis cinerea,Gaeumannomyces gramini,Fusarium fujikuroi,Fusarium sulphureum,Phytophythora capsici and Colletrichum lagenarium were investigated through mycelium growth rate method.Both drimenal and drimenol possessed good activities,especially for drimenal with it's inhibition rates of 62.26%,61.37%and 65.08%respectively against Rhizoctonia solani,Sclerotinia sclerotiorum,and Botrytis cinerea at a concentration of 50?g/mL.(2)With drimanol as a lead compound,ester and carbamate functional groups were introduced into C11 position for the structure optimization,in which 21 compounds were designed and synthesized.The structures were determined based on LC-MS,1H-NMR and 13C-NMR.The fungicidal activities against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum and Botrytis cinerea were investigated through mycelium growth rate method.The results demonstrated that the synthesized chiral drimanes showed weaker activities on all the tested fungi in copmarison with drimanol.(3)8-OH-Drimanol was functionalized with ether group,ester group and carbamate activity group on C11 position for the structure optimization,and 47 compounds were designed and synthesized.The structures were determined based on LC-MS,1H-NMR and 13C-NMR.The fungicidal activities of the deriatives against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum and Botrytis cinerea were investigated and the EC50 values were further confirmed.The results demonstrated that the synthesized chiral drimane carbmate deriatives 6a and 6b showed good activities against Botrytis cinerea with it's EC50 values of 11.39?g/mL and 12.62?g/mL respectively.(4)The drimane fused oxazinone,which was obtained from the rearrangment of amide or hydrozide,was employed as the lead compound for further structure optimization with N-substitution as a key step,23 compounds were synthesized and determined based on LC-MS,1H-NMR,13C-NMR,and DEPT 135 and the structures of 7o and the other derivatives were further confirmed through X-ray single crystal diffraction.The preliminary antifungal activities of the deriatives against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum,Botrytis cinerea,Alternaria solani and Fusarium fujikuroi were investigated and the EC50 values were forther confirmed.Compound 7j exhibited excellent antifungal activities against all the tested fungi,among which the EC50 value of compound 7j against Botrytis cinerea was as low as 1.18?g/mL.The antibacterial activities of this kind of alkaloids against Xanthomonas oryzae pv.oryzae,Bacillus subtilis,Erwinia carotovora,Xanthomonas oryzae pv.oryzicola,Ralstonia solanacearum,Pseudomonas syringae pv.Lachrymans and Clavibacter michiganensis subsp.sepedonicus were investigated through filtering paper method,and MIC values of these deriatives against Bacillus subtilis,Xanthomonas oryzae pv.oryzicola and Ralstonia solanacearum were further evaluated,among which compound 7m exhibited much better activities against Bacillus subtilis,Xanthomonas oryzae pvoryzicola and Ralstonia solanacearum with it's MIC values of 8?g/mL,12.5?g/mL and 8p,g/mL respectively than that of the positive control streptomycin sulphate(with it's MIC values of 25?g/mL,100?g/mL and 50?g/mL respectively).(5)The homodrimane sesquiterpenoids were designed and synthesized through oxidative degradation or reduction and hydrolysis reactions with(-)-sclareol or(+)-sclareolide as a starting material.Five series,including 73 homodrimane sesquiterpenoid derivatives were designed and synthesized by ether group,ester group,carbamate and amide activity group.The structures were determined based on LC-MS,1H-NMR,13C-NMR and DEPT 135,and the structures of 12b and 12n were further confirmed by X-ray single crystal diffraction.The preliminary antifungal activities against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum and Botrytis cinerea were investigated and the EC50 values were further confirmed.The result indicated that homodrimanyl amide deriatives presented excellent antifungal activities.Moreover,chirality and OH of C8 position are crucial for the antifungal activity.(6)The inhibition-structure-activity relationship of homodrimanes was discussed through 3D-QSAR for further optimization.The protective effect of compound 12i and it's diastereoisomer 8-epi-12i against Botrytis cinerea resulted in 47.61%and 50.00%in vivo at a concentration of 200?g/mL,which were suporior than that of the positive control(carbendazim:35.71%).Inclusion,the active sesquiterpenoid drimenal and it's analogues were synthesized with the natural diterpene(-)-sclareol as a starting material.The structures of drimane sesquiterpenoid analogues were designed and synthesized.Totally 177 compounds were synthesized,of which the target products 166,and 160 were new.The disscussion of inhibition-structure-activity relationship lay a solid foundation of developing novel fungicidal candidates with drimane lead scaffold.