Synthesis And Biological Activities Of Novel Tetramic Acid Derivatives Incorporating A Moiety Amino Or Hydrazino

The naturally occurring tetramic acids with diversified structures have been isolated from land and ocean organism and were found to exhibit antitumor, antiviral, antibacterial and herbicidal activities. As one superior example of them, tenuazonic acid is a metabolic toxin of Alternaria alternata (Fr.) Keissler. Much interest has been focused on this natural compound because of its broad spectrum of biological activity. By modifying the groups on pyrrolidine-2,4-dione ring, a lot of tetramic acid derivatives possessing good biological activities have been synthesized. Amino, hydrazino and hydrazone were common groups in structures of pesticides, have played a critical role in the research and development of new pesticides. In order to screen the compounds showing better biological activities, amino, hydrazino and hydrazone were introduced to3-position of tetramic acid, respectively, to design and synthesize115novel tetramic acid derivatives with tenuazonic acid as a leading compound. Their fungicidal and herbicidal activities were also evaluated.First, the intermediate3-(1-hydroxyethylidene)-5-sec-butyl-pyrrolidine-2,4-dione (4) was prepared by the reaction of esterification,N-aceto-acetylation and cyclization with L-isoleucine as a starting material. It was noted that the epimerization at the position C-5occurred during the cyclization to give a diastereoisomer of tenuazonic acid and its (5R,6S)-isomer. The compound4was reacted with substituted amines or hydrazines to afford285-sec-butyl-3-(1-substitutedamino)ethylidene-pyrrolidine-2,4-diones Ⅰ and165-sec-butyl-3-(1-(2-substitutedhydrazinyl)ethylidene)pyrrolidine-2,4-diones Ⅱ, respectively. Subsequently, the compound Ⅱ were cyclized or reacted with the formaldehydes and ketones, respectively, to give86-sec-butyl-3-methyl-1-substituted pyrrolo[3,4-c]pyrazol-4-ones Ⅲ,175-sec-butyl-3-(1-(2-substituted methylene-hydrazinyl)ethylidene)pyrrolidine-2,4-diones IV, and115-sec-butyl-3-(1-(2-(1-substituted ethylidene)hydrazinyl)ethylidene) pyrrolidine-2,4-diones V. The structures of all target compounds were confirmed by IR,1H NMR, MS and elemental analysis. The crystal structures of Ⅰ-13, Ⅰ-25, Ⅲ-6and Ⅳ-8were characterized by X-ray diffraction. The absolute configuration of5S,6S-isomer and the5R,6S-isomer were confirmed. They formed different dimers by intermolecular hydrogen bonds.The herbicidal activities of the target compounds Ⅰ, Ⅱ, Ⅲ, Ⅳ and Ⅴ were determined with B. campestris and E. crusgalli at the concentration of100mg/L. The results showed that some of the compounds possessed certain herbicidal activities. Thereinto, the compound Ⅰ-23showed excellent herbicidal activity with a inhibitory rate of94.4%against the root of B. campestris. The compound Ⅱ-1showed a inhibitory rate of86.3%against the root of E. crusgalli. But their herbicidal activities were lower than that of the intermediate4.In addition, the compounds Ⅰ, Ⅱ, Ⅲ, Ⅳ and Ⅴ were screened for antifungal activities in vitro against selected phytopathogenic fungi, F. graminearum, B. cinerea, R. cerealis and C. capsici at the concentration of100mg/L. The results showed that the compounds Ⅱ exhibited remarkable fungicidal activities against tested fungi. Thereinto, the compound Ⅱ-10displayed highest inhibition activities against four kinds fungi with EC50values of0.7679mg/L,0.7638mg/L,0.1154mg/L and0.7356mg/L, respectively. The EC50value of the compound Ⅱ-10against R. cerealis was more three times than that of hexaconazole (0.0375mg/L).With the compound Ⅱ as secondary leading compound,1-substituted and5-substituted tetramic acids were prepared by the structure modifying to the intermediate4at the1-position or5-position. They were reacted with4-F,4-C1and4-Br phenylhydrazine, respectively, to afford353-(1-(2-(4-halogensubstitutedphenyl)hydrazinyl)ethylidene) pyrrolidine-2,4-diones Ⅵ. Their structures were confirmed by IR,1H NMR, MS and elemental analysis.1H NMR spectrogram revealled that the compounds Ⅵ-1-Ⅵ-17contained two isomers of Z-configuration and E-configuration. And E-configuration was found to be a stable configuration by means of2-D NOSEY spectrogram. Furthermore, the structure of Ⅵ-19was confirmed by X-ray diffraction.At the concentration of100mg/L, the compounds6displayed some inhibition activities against the root of E. crusgalli. The inhibition rates of the compounds Ⅵ-11and Ⅵ-22all reached68.3%corresponding. But the inhibition rates of all the compound Ⅵ were less than the intermediate4against the root of B. campestris and the bud of E. crusgalli. The results of fungicidal activities indicated the compounds VI exhibited prominent fungicidal activities against above four fungi. The EC50values of the compound Ⅵ-2against F. graminearum and B. cinerea were0.2702mg/L and0.7937mg/L, respectively. The EC50values of the compound Ⅵ-3against R. cerealis and C. capsici were0.0382mg/L and0.2367mg/L, respectively. And the EC50value of the compound Ⅵ-2against F. graminearum was lower than that of carbendazim (0.4071mg/L). Moreover, the EC50value of the compound VI-3against R. cerealis was lower than that of flutolanil (0.3320mg/L), close to that of hexaconazole (0.0375mg/L), and its EC50value against C. capsici was also close to that of azoxystrobin (0.2153mg/L).