Synthesis And Biological Activity Of Tetramic Acid Derivatives Containing Butyrohydrazide And Ester Moieties

Tetramic acid derivatives,containing the heterocycle of pyrrolidine-2,4-dione or pyrroline-2-one,often exhibit a wide range of biological activities including antibacterial,antiviral,antioxidant and antitumor activity,and attact more and more attention of scientists.The compounds with acylhydrazide or ester moiety occupy a very important position in the development of pesticides because of their various activities.In this paper,butyrohydrazide and ester moieties were introduced to 3-position and 4-position of pyrrolinone respectively to design and synthesize three series of thirty-one novel tetramic acid derivatives.Their fungicidal activities were also evaluated.Pyrrolidine-2,4-dione 6 was prepared firstly by esterification,amidation,Dieckmann cyclization and decarbonylation with glycine as the starting material.Then the intermediate 4-(2,4-dioxopyrrolidin-3-ylidene)-4-hydroxybutanoic acid 8 was obtained by the reaction of compound 6 with ethyl succinyl chloride and the hydrolysis reaction.Compound 8 and aniline were dissolved in ethanol and refluxed to give 4-(2,4-dioxopyrrolidin-3-ylidene)-4-(phenylamino)butanoic acid 9.Compound 9 was cyclized oneself to gain 1-phenyl-1',3,4,5'-tetrahydro-[2,3'-bipyrrolylidene]-2',4',5(1H)-trione 10.Compound 10 was reacted with substituted phenylhydrazine to get seven butyrohydrazide derivatives containing pyrrolidine-2,4-dione and phenylamine moieties 11.Finally,compound 11 was reacted with different chloroformates respectively to synthesize novel thirty-one tetramic acid derivatives containing butyrohydrazide and ester moieties.Their structures were characterized by 1R,1H NMR and MS.The fungicidal activities of all the target compounds against Fusarium graminearum,Botrytis cinerea,Rhizoctonia solani and Colletotrichum capsici were evaluated with the mycelial growth rate method.Some target compounds showed remarkable inhibitory activity at 1?g/mL.The ECso values of some selected compounds were determined.The EC50 values of compounds A2,A4,A6,B2 and B5 were lower than 1?g/mL against F.graminearum.Among them,compound A4 showed the highest activity with the EC50 value of 0.3217?g/mL,lower than 0.4743?g/mL of carbendazin.The EC50 values of compounds A2 A4,A6,A13,A14,A16,A17,B4,B5 and C8 were lower than 1 pg/mL against B.cinerea.The compounds A4 and A16 are most striking with the EC50 values of 0.2839?g/mL and 0.3652?g/mL,lower than 1.3328 pg/mL of azoxystrobin.The EC50 values of compounds A1-A6,A13-A15,A17,B2,B3 and C8 were lower than 1?g/mL against R.solani.The compounds Al,A2 and A5 showed conspicuous activity with the EC50 values of 0.1284 ?g/mL,0.1497?g/mL and 0.1666?g/mL,lower than 0.4219?g/mL of carbendazin.Besides,the EC50 values of compounds A2-A4?A6?B2?B3 and C7 were lower than 1?g/mL against C.capsici.The compounds A3 and A4 exhibited obvious activity with the EC50 value of 0.6247?g/mL and 0.5352?g/mL.The preliminary structure-activity relationship analysis indicated that the target compounds containing halogen substituent at 4-position of phenyl ring of phenylhydrazine showed higher antifungal activity.