Synthesis And Fungicidal Activities Of Sustituted Phenylhydrazine Derivatives Incorporating 1-(UN)Substituted Tetramic Acid

The naturally occurring tetramic acids have been isolated from many marine and terrestrial lives, and were found exhibiting antitumor, antiviral, herbicidal and fungicidal activities. Massive derivatives of tetramic acid were synthesized and some of them showed significant biological activities. In this article, substituted phenylhydrazines were introduced to 3-position of 1-(un)substituted tetramic acids to synthesize 49 novel 1-(un)substituted-3-(1-(substituted benzylhydrazinyl)ethylidene)pyrrolidine-2,4-dione derivatives, and their fungicidal activities were also preliminarily evaluated.The intermediates 3-(1-hydroxyethylidene)pyrrolidine-2,4-dione and 1-methyl-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione were prepared by the reaction of esterification, N-acetylation and cyclization with glycine and sarcosine as starting materials. The intermediates 1-ethyl-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione and 1-benzyl-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione were prepared by the reaction of N-substitution, esterification,N-acetylation and cyclization with ethyl bromo acetate, ethylamine and benzylamine as starting materials. Four kinds of tetramic acids were reacted with substutited benzylhyrazines to give forty-nine 1-(un)substituted-3-(1-(substituted phenylhydrazinyl)ethylidene)pyrrolidine-2,4-diones. The structures of these title compounds were confirmed by IR, 1H NMR, MS and elemental analysis.The fungicidal activities of all title compounds against Fusarium graminearum, Botrytis cinerea, Rhizoctonia cerealis and Colletotrichum capsici were evaluated by mycelial growth rate method The results indicated that most compounds showed notable fungicidal activities at the concentrations of 100 μg/mL and 10 μg/mL. The compounds with group of 4-F,4-Cl,4-Br or 2,4-(Cl)2 at benzene ring of 3-position of pyrrolidine-2,4-dione exhibited much better fungicidal acitivities against four kinds of fungi. The EC50 values of some selected compounds were determined. The compounds A9, C2, C3, C4 and C12 exhibited high fungicidal activities against 4 kinds of fungi and the the EC50 values against four fungi were all lower than 1.0 μg/mL. The EC50 values of the compound C12 against B. cinerea, R. cerealis, C. capsici were 0.2406 μg/mL,0.1791 μg/mL and 0.1876 μg/mL, lower than the EC50 values of procymidone(0.2595 μg/mL), flutolanil(0.3541 μg/mL) and azoxystrobin(0.2595 μg/mL), respectively. The compound A9 showed highest activity against F. graminearum with the EC50 value of 0.4029 μg/mL, equal to the EC50 value of carbendazim(0.3917 μg/mL). The compound C12 showed highest activity against B. cinerea with the EC50 value of 0.2406 μg/mL, lower than that of procymidone(0.2595 μg/mL). The EC50 values of the compounds B11 and D11 against R. cerealis were 0.0876 μg/mL and 0.0866 μg/mL, lower than the EC50 value of flutolanil(0.3541 μg/mL). The EC50 values of the compounds C5 and C12 against C. capsici were 0.1754 μg/mL and 0.1876 μg/mL, lower than the EC50 value of azoxystrobin(0.2498 μg/mL). The preliminary structure-activity relationship analysis showed that substitution group at the benzene of phenylhydrazine had a remarkable effect on fungicidal activity, the overall order of fungicidal activity is as follow:4-F,4-C1,4-Br,2,4-(Cl)2>2-F,3-Cl>4-H, 4-CH3,4-CH3O,3,4-(CH3)2,4-NO2>2,4-(NO2)2>4-NH2SO2. At the same time, fungicidal activity was also greatly influenced by the substituent at 1-position of pyrrolidine, the overall order of fungicidal activity is as follow:hydrogen≈ethyl>methy>benzyl.