Biomimetic Design,Synthesis,Biological Activities And Structure-activity Of Novel QBAs Analogues And Its Derivatives

Quaternary Benzo[c]phenanthridine alkaloids(QBAs)are distributed in Papaveraceae and Fumariaceae plant et al.Natural QBAs have been a research hot spot for their special structure,extensive bioactivities and the number of rare.Sanguinarine(SA)and Chelerythrine(CH)are the representative compounds of QBAs.Our previous studies demonstrated that SA and CH have antitumor,antifungal,antibacterial and acaricidal activities.But,few in number and active in chemical property are one of the main limits of the application and development of natural QBAs.Thus,one hundred and nine QBAs analogues and their derivatives were designed and synthesized in this paper using SA and CH as the template.Sixty-five compounds of them were evaluated for antifungal activities in vitro against 12 phytopathogens and the structural-activity relationship was identified.Some higher active compounds were subjected to fungicide toxicity assay.Then,some better compounds of them were continued study by tissue culture and pot experiment and several new antifungal compounds with the value of direct or indirect application were found.Meanwhile,in vitro antibacterial activity and in vitro acaricidal activity of QBAs-like compounds were assayed,the structure-activity relationship of the compounds was carried.This thesis concludes as followings:1.A novel and efficient approach for the synthesis of QBAs-like compounds and their derivatives was developed from commercially available 1,3-benzodioxole through 10 reactions,such as Blanc Chloromethylation,Substitution Reaction,hydrolysis reaction,reduction reaction,Cyclization and oxidation reaction et al.Forty-five simple QBAs-like compounds(2-Aryl-3,4-dihydroisoquinolin-2-iums,named compounds A),64 derivatives of QBAs-like compounds were synthesized by this methodology(compounds B,compounds C and compounds M).Sixteen 2-aryl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile(namely compounds B),five 1-alkoxy-2-aryl-1,2,3,4-tetrahydroisoquinoline(compounds C)and 432-aryl-1,2,3,4-tetrahydroisoquinoline(compounds M)are included in the 64 derivatives.All the 109 compounds were elucidated by MS,HRMS,IR,1H-and 13C-NMR analysis,of which 102 compounds were the first time to report.2.Sixty-five compounds were evaluated for antifungal activities in vitro against 12 phytopathogens at 50 ?g/mL by mycelial rate growth assay.The result showed all the compounds A and their derivatives possessed broad-spectrum of antifungal activities,All the compounds showed activity against all the test fungi in varying degrees at 50 ?g/mL,and some compounds showed higher activities than Thiabendazole(TBZ).The higher active compounds were subjected to fungicide toxicity assay.Some compounds showed exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine,they are worth further researth.Among them,Seventeen compounds showed the best antifungal activities in the all screened compounds for Fusarium solani,including A33,A10,A35 etc.The EC50 of these compounds were 2.01 ?g/mL?10.30 ?g/mL;For Curvularia lunata,Eight compounds such as A2?A3?A6 etc have good activities,The EC50 of these compounds were 3.43 ?g/mL?7.23 ?g/mL;A38 and A31 showed the best antifungal activities in the all screened compounds for Fusarium graminearum and Valsa mali.Their EC50 were 6.73 ?g/mL and 7.35 ?g/mL.The structure-activity relationship indicated that the iminium moiety(C=N+)in QBAs-like compounds was the key structural moiety for their antifungal activity.Thesubstituent of methylenedioxy in the ring A and the substituent of halogen in ring C could enhanced the activity.Generally,o-substituted and m-substituted isomers were more active than p-substituted isomer.3.On this base,The antifungal activity of A38 against Valsa mali and Clanerela cinyulate were evaluated by tissue culture in apple.The result showed that A38 have a good resistance for the two fungi,Their EC50 were 3.16 ?g/mL and 1.16 ?g/mL.4.A pot experiment was conducted to study the in vivo antifungal activity of A on Curvularia lunata,The result showed that A could prevent Curvularia lunata remarkably,3 compounds give the-best control effect(A3:84.4%;A8:79.7%;All:79.7%).5.The crop security trails confirmed that almost all the tested compounds were safe for P.miliaceum L.and B.campestris L.And compounds A31-A35 could enhanced the growth of the crop's root and stem when the using concentration lower than 100 ?g/mL.6.In vitro antibacterial activity on Escherichia coli and Staphylococcus aureus of compounds QBAs was evaluated by broth dilution method.The result showed compounds A have weaker inhibitory rate than Ceftriaxone Sodium and ciprofloxacin.For E.coli,A6 showed the highest activity,the minimal inhibitory concentration(MIC)was 1.25 mg/L.For S.aureus,A9 and A10 displayed the best activity(MIC = 20 mg/L).The structure-activity relationship indicated that the iminium moiety(C=N1)in QBAs-like compounds was the key structural moiety for their antibacterial activity,too,and the presence of electron withdrawing groups in ring C could enhance the activity.7.In vitro acaricidal activity was assayed with dipping insect method against Tetranychuscinnbarinus(plant mite).Compounds A displayed the activity in varying degrees in 1mg/mL.A6 have the highest mortality rate(47.2%),but the data was much lower than the mortality rate of ivermectin.This is a firstly systematic study on QBAs-like compounds for their molecular design,synthesis,antifungal activity and acaricidal activity et al by the strategy of biomimetic synthesis.Some new,safe,efficient antifungal compounds were found.All of the research results will be of important significance to develop fresh antifungal agents for plants.