Acaricidal And Antifungal Activities And Structure-actibity Relationship Of Cinnamic Acid Esters And Its Derivatives

Cinnamate and its derivatives,found among many different plants,have attracted pharmacologists'attention due to their variety of important pharmacological activities such as anticancer,antimicrobial,antioxidative,antiviral,anti-human immunodeficiency virus(H?V),etc.However,few research on cinnamic acid derivatives,which characterized by low-toxic and environment-friendly,and their anti-phytophathogenic fungi and acaicidal activity against P.cuniculi were reported.?n order to extend the activities and application of cinnamate and its derivatives,our research focus on their molecule design and synthesis as well as their structure-activity relationship(SAR)from a comprehensive and systematic prospect.?n this study,a series of cinnamic acid derivatives were prepared and evaluated for anti-phytophathogenic fungi activity and acaicidal activity against P.cuniculi.The results of this thesis are listed as follows:1.Totally 166 cinnamic acid derivatives including 104 cinnamate and its analogues(series ?),54 dihydrogenized cinnamate and its analogues(series ?)and 8 other analogues(series ?)were designed and synthesized.Their structures were identified by ¹H-NMR,¹³C-NMR and MS.2.Acaricidal activity in vitro against Psoroptes cuniculi of the compounds(?O,?H,?and?)was assayed by dipping mite method.The results showed that all 107 tested compounds showed acaricidal activity in varying degrees at the concerntration of 0.5 mg/m L.Among them,33 compounds showed higher activity with median lethal concentrations(LC₅₀)of 27.3-192.1?g/m L and median lethal time values(LT₅₀)of 0.7-15.3 h at 4.5?mol/m L,respectively,than ivermectin(LC₅₀=247.4?g/m L),a standard acaricidal drug.Six compounds exhibited LC₅₀values of<50?g/m L.Compound??O 1 showed the highest activity(27.3 g/m L),and its relative activities(RA)reached up to 9.1-fold the activity of ivermectin.Compound??O 27 displayed quick-acting property to the mites(LT₅₀<0.7 h).3 The structure-activity relationship(SAR)of analogues or derivatives of cinnamic acid esters on their acaricidal activity was discussed.(1)The comparison of the?series and the??series shows that the carbon–carbon double bond in the acrylic ester moiety was proven not to be essential to improve the activity.(2)The substitution will exert different effects on acaricidal activity due to its location and genre.The chain length and branching degree of the alkyl group in the alcohol moiety,the steric hindrance around the ester group and 3-phenyl ring will exert significantly influence on their activities.Therefore,a less steric hindrance means a higher activity.(3)Compared with esters,the much less contribution to activity made by substituent of thiols,amides,ketones,ethers and acids indicating that the ester group is an irreplaceable active group;(4)The replacement of phenyl groups in cinnamic acid esters with 2-pyridyl group and 2-furan group will substantially enhance the activity,which can be speculated that the hydrogen bond make most contribution to it.(5)The direct connection of phenyl and ester group will decrease the activity,while the insertion of 2 to 4 methylenes exert little impact to the activity.4.Seventy-two compounds(?O and?P)were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method.Kresoxim-methyl,(KM),a commercial fungicide,were used as a positive control.Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 m M.Ten compounds showed the higher activity with average EC₅₀ values of 17.4-43.0?g/m L for the fungi than koroxim-methyl,a commercial fungicide standard.Compounds?P 35 and?P 36produced the higher activity with average EC₅₀ values of 17.4 and 18.5?g/m L and great potential for development of new plant antifungal agents.5.The structure-activity relationship(SAR)of cinnamic acid esters and their derivatives was discussed:Both substitution patterns of the benzene ring and the type of alkyl groups in the alcohol moiety significantly influence the activity of compounds.1)For ethyl cinnamate derivatives,in most cases,the introduction of substituents to the benzene ring leads to increase of the activity.For electron-donating groups like OH,OMe,and OAc,the order of the activity of various position isomers is o-substituted isomer>p-substituted isomer>m-substituted isomer,whereas for electron-withdrawing groups like halogen atoms and trifluoromethyl,psubstituted isomers generally have the highest activity.2)The higher steric hindrance near the ester group is helpful to improvement of the activity.3)There is a complex comprehensive effect between the substituent on the phenyl ring and the alkyl group in the alcohol moiety on the activity.The combinations of“2-OH,4-OH or 2-OAc+t-butyl or t-amyl”will activate synergistic enhancement effect,which can increase their activity.On the contrary,the combinations of“2-OMe,4-OMe,2-OH-3-OMe,4-F,4-Br,4-CF3 or 3,4-OCH2O+t-butyl or t-amyl”generally decrease the activity.?n conclusion,the results show that these compounds demonstrate great potential for the development of novel anti-mite and antibacterial agents.?t is necessary to get a further study on the mechanism of the compounds.