Synthesis And Biological Activity Of Tetramic Acid Derivatives Incorporating Phenylpyrrole Or Butyrohydrazide Moiety

Tetramic acid derivatives,the heterocyclic core of which is pyrrolidine-2,4-dione or 4-hydroxy-1H-pyrrol-2(5H)-one,usually exhibit a wide range of biological activities including antioxidant,antitumor,antiviral,herbicidal and antifungal activity.The compounds with an aniline,pyrrolin-2-one,pyrrole or acylhydrazide moiety occupy a very important position in the research and development of new pesticides because of their various activities.In this paper,aniline,pyrrolin-2-one,pyrrole and butyrohydrazide moieties were introduced to 3-position of pyrrolidine-2,4-dione respectively to synthesize four series of sixty-seven novel tetramic acid derivatives.Their fungicidal and insecticidal activities were also evaluated.Firstly,pyrrolidine-2,4-dione 5 was prepared through esterification,N-acylation,Dieckmann cyclization and decarboxylation.The intermediate 4-(2,4-dioxopyrrolidin-3-ylidene)-4-hydroxybutanoic acid 7 was obtained from compound 5 by successively performing the acylation using ethyl 4-chloro-4-oxobutanoate,saponification with 10%aqueous sodium hydroxide and acidification using 10%aqueous hydrochloride.Compound 7 and substituted aniline were dissolved in ethanol and refluxed to give twelve 4-(2,4-dioxopyrrolidin-3-ylidene)-4-(substituted phenylamino)butanoic acids 8.Then the synthesis of twelve 1-(substituted phenyl)-1',3,4,5'-tetrahydro-[2,3'-bipyrrolylidene]-2',4',5(1H)-triones 9 were carried out via intramolecular cyclization of compounds 8 using EDCI as the condensation agent and DMAP as the catalyst.Finally,ninety dialkyl 1-(substituted phenyl)-2'-oxo-2',5'-dihydro-1H,1'H-[2,3'-bipyrrole]-4',5-diyl bis(carbonates)10 and twenty-four N'-(substituted phenyl)-4-(2,4-dioxopyrrolidin-3-ylidene)-4-((substituted phenyl)amino)butanehydrazides 11 were conveniently obtained by the reactions of 9 with different chloroformates or substituted phenylhydrazines,respectively.Their structures were characterized by IR,1H NMR,13C NMR,MS and elemental analysis.The structure of 10b was confirmed by X-ray diffraction crystallography.The fungicidal activities of the target compounds against Fusarium graminearum,Botrytis cinerea,Rhizoctonia solani and Colletotrichum capsici were evaluated in vitro by mycelial growth rate method.The compounds 8 and 9 showed certain activity at the concentration of 100 ?g/mL.Among them,compound 9d showed high activity against B.cinerea with the inhibitory rate of 71.4%.The compounds 10 were more sensitive to tested fungi than the compounds 8 and 9.Compound 10h showed the highest activity against B.cinerea with an inhibitory rate of 82.2%,while compound 10d showed the highest activity against R.solani with an inhibitory rate of 78.7%.The structure-activity relationship analysis showed that medium-sized alkyls at alcohol part of the carbonate moiety may elevate the antifungal activity of compounds 10.Moreover,the compounds 11 exhibited remarkable fungicidal activities against the tested fungi.The EC50 values of some selected compounds were determined.The EC50 values of compounds lla-11c,11g,11h,11j,11o and 11r were lower than 1 ?g/mL against all tested fungi.Among them,compound 11a showed highest activity against F.graminearum with the EC50 value of 0.2693 ?g/mL,lower than 0.6794 ?g/mL of carbendazin.The compound 11a also showed highest activity against B.cinerea with the EC50 value of 0.4078 ?g/mL.The compound llr showed highest activity against R.solani with the EC50 value of 0.0193 ?g/mL,lower than 0.5799 ?g/mL of carbendazin.And the compound lln showed highest activity against C.capsici with the EC50 value of 0.1773?g/mL,lower than 0.3488 ?g/mL of azoxystrobin.The structure-activity relationship analysis showed that the compounds containing halogen substituent at 4-position of phenyl ring of phenylhydrazine exhibit higher antifungal activity.The insecticidal activities of the target compounds against Plutella xyllostella and Aphis fabae were evaluated by leaf disk dip method and slide dip method,respectively.At the concentration of 100 ?g/mL,compound 1 Or showed the highest activity with a mortality rate of 50.77%against Aphis fabae,while compound llo showed the highest activity with a mortality rate of 50.00%against Plutella xyllostella.