酰胺类KARI酶抑制剂的设计、合成和生物活性

Design and Synthesis of Amide KARI Inhibitors and Their Biological Activities

以分子对接法进行MDL/ACD三维数据库搜寻所得到的大量结构信息为指导,从中选取部分酰胺类小分子进行化学合成和结构表征.生物活性测试结果表明,设计合成的8个酰胺类化合物在200μg/mL浓度下对水稻KARI酶具有不同程度的抑制活性,化合物1和6的抑制率可达到57.4%和48.1%.部分化合物在100μg/mL浓度下对双子叶植物油菜的胚根和单子叶植物稗草的茎叶的抑制活性较为显著,化合物1和6对油菜胚根生长抑制率分别为52.0%和72.6%,其与KARI酶体外(invitro)抑制活性具有一定的相关性.这些酰胺类化合物可作为KARI酶抑制剂为后续分子设计提供借鉴.

Ketol-acid reductoisomerase（KARI） is a promising target for the design of herbicides, however, there are only few literatures about the molecular design of KARl inhibitors. In this paper, on the basis of the reported 0. 165 nm high resolution crystal structure of spinach KARl complex, 279 molecules with a low binding energy toward KARl were obtained from MDL/ACD 3D database searching by program DOCK 4.0. According to the structural information of 279 molecules provided, some amide compounds were synthesized. The bioassay results show that most of these amides had an inhibitory activity to rice KARl at a test concentration of 200 μg/mL, Among the eight amides synthesized, compounds 1 and 6 showed 57.4% and 48.1% inhibitory activity to KARI. The herbicidal activities of these amides were further investigated on di-cotyledonous rape （ Brassica campestris） and mono-cotyledonous barnyardgrass （ Echinochloa crusgalli）. Compounds 1 and 6 were more favorable than others and showed 52.0% and 72.6% inhibitory activity on rape root at 100 μg/mL concentration, which was correlated with their in vitro activity to KARl. These amides KARl inhibitors designed can be further optimized for finding more potent KARl inhibitors and herbicide candidates as well.