title: Synthesis, bioactivity, theoretical and molecular docking study of 1-cyano-N-substituted-cyclopropanecarboxamide as ketol-acid reductoisomerase inhibitor.
abstract: Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) catalyzes the second common step in branched-chain amino acid biosynthesis. The catalyzed process consists of two stages, the first of which is an alkyl migration from one carbon atom to its neighbouring atom. The likely transition state is a cyclopropane derivative, thus a series of new cyclopropane derivatives, such as 1-cyano-N-substituted-cyclopropanecarboxamide, were designed and synthesized. Their structures were verified by (1)H NMR, FTIR spectrum, MS and elemental analysis. The K(i) values of active compounds 2, 4b against rice KARI were 95.30+/-13.71, 207.9+/-21.99 microM, respectively. The X-ray crystal structure of compound 4a was also determined. Auto-Dock was used to predict the binding mode of 4a. This was done by analyzing the interaction of the compounds 4a with the active sites of spinach KARI. This result was in accord with the result analyzed by the frontier molecular orbital theory.
authors.affiliation: The Research Institute of Elemento-Organic Chemistry, The State-Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, Nankai University, Tianjin 300071, China.
authors.forename: Xing-Hai
authors.initials: XH
authors.lastname: Liu
authors.forename: Pei-Quan
authors.initials: PQ
authors.lastname: Chen
authors.forename: Bao-Lei
authors.initials: BL
authors.lastname: Wang
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Wang
authors.forename: Zheng-Ming
authors.initials: ZM
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D050540:Ketol-Acid Reductoisomerase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D012275:Oryza / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D008024:Ligands; C030797:cyclopropane; D050540:Ketol-Acid Reductoisomerase