Studies on the Synthesis, Structure and Biological Activities of Novel Arylaminoformyl-containing 1-Cyano-1-cycloproane Carboxylic Acid Amides Based on Ugi Reaction
Received date: 2015-05-20
Online published: 2015-11-19
Supported by
Project supported by the National Natural Science Foundation of China (No. 21372133) and “111” Project of Ministry of Education of China (No. B06005).
As one of key enzymes that catalyze the biosynthesis of branched-chain amino acids in plants and microorganisms (bacteria, fungi), ketol-acid reductoisomerase (KARI; EC 1.1.1.86) can be regarded as a promising target for designing herbicides or fungicides. Previously, we have found that N-aryl-1-cyano-1-cyclopropane carboxamides and cyclopropylformyl thioureas exhibit favorable KARI inhibitory activity and can be made further structure modification for discovery more new inhibitors. In this continuous work, a series of novel 1-cyano-1-cycloproane carboxylic acid amides containing arylaminoformyl moity 8a～8p were designed accordingly and synthesized via one-pot Ugi reaction with 1-cyano-1-cyclo- propane carboxylic acid, aryl isonitrile, aldehyde and amine as reactants. The structures of the new compounds were confirmed by 1H NMR, 13C NMR, IR spectra and elemental analysis or HRMS. Meanwhile the crystal structure of 8m was reported, which provided comprehensive structure information for this kind of compounds. From a continuous assay method that following the consumption of NADPH (involved in the KARI-catalyzed reaction) at 340 nm, it was found that most of these cyclopropane diamide derivatives exhibit obvious KARI inhibitory activities and are new KARI inhibitors, among which 8a～8c, 8m, 8n and 8j possessed inhibition rate of 94%～98% at a test concentration of 200 mg/L against rice KARI, and 8m had a Ki value of (77.91±30.15) μmol/L. These new inhibitors synthesized in this paper can inhibit KARI enzyme effectively at the same level with those of N-aryl-1-cyano-1-cyclopropane carboxamides reported previously. In addition, the preliminary bioassay results also showed that several compounds exhibit significant in vitro fungicidal activities at a test concentration of 50 mg/L against Ftasarium omysporum, Cercospora arachidicola, Physalospora piricola, Alternaria solani and Gibberella sanbinetti by using the mycelium growth rate test method, and 8e and 8p, which have comparatively broad fungicidal spectrum on the whole and are comparable with the contrast Triadimefon during the present study, could be used as novel hit compounds for further structural optimization in fungicide innovations.
Zhan Yizhou , Wang Baolei , Zhang Liyuan , Zhang Yan , Zhang Xiao , Li Zhengming , Song Haibin . Studies on the Synthesis, Structure and Biological Activities of Novel Arylaminoformyl-containing 1-Cyano-1-cycloproane Carboxylic Acid Amides Based on Ugi Reaction[J]. Acta Chimica Sinica, 2015 , 73(11) : 1173 -1181 . DOI: 10.6023/A15050333
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