苯并噻唑缩醛衍生物合成及除草作用机制研究

Molecular structural optimization based on lead compounds is one of the main approaches to the development of novel pesticides. Benzothiazole N,O-acetal is a novel compound discovered in our laboratory previously, and it showed good herbicidal activity against broadleaf weeds. However, the herbicidal activity of the lead compounds cannot meet the requirement for industrialization at this stage, and the improvement of activity by structural modification is promising, and and the mechanism of action is unknown. In view of the existing problems, this project intends to carry out two aspects of research. (1) Candidates for herbicides which targeted on broadleaf weeds will be designed and synthesized by using the techniques of computer-aided drug design. Strategy of structural optimization will be focused on the benzene ring, 2-amino group of benzothizole and side chain, respectively. (2) Investigation on the mode of action of the candidates will be carried out by using the multi-endpoint assay, and in which single cell green algae is used as the model organism. After be treated with subcytotoxic concentration of compounds, the physiological and biochemical endpoints of the tested unicellular algae will be monitored, and the mechanism can be clarified based on these results. The results of the study is expected to clarify the relationship between herbicidal activity and chemical structure of benzothiazole N,O-acetal, and the candidate compounds of herbicides will be obtained, and its mechanism of action will be determined.

基于先导化合物的分子结构优化是新农药开发的主要途径之一，苯并噻唑氮氧缩醛是申请人在前期研究中发现的对阔叶杂草具有很好除草活性的新型先导化合物，但其除草活性距离产业化仍有距离，通过结构改造提升活性的空间很大，且作用机制亦不清楚。本项目拟采用计算机辅助药物设计技术，针对先导化合物的骨架苯环、苯并噻唑的2-位氮原子以及缩醛侧链三个部位分别进行结构优化，针对阔叶杂草设计合成除草剂候选化合物；采用多端点评价体系，以亚细胞毒性剂量的候选化合物处理单细胞绿藻，测定其多个生理生化指标的变化，确定化合物的作用部位。该项目研究结果预期可阐明苯并噻唑氮氧缩醛类化合物的化学结构与除草活性之间的关系，获得具有应用价值的除草剂候选化合物，并确定其作用部位。

本项研究设计合成了苯并噻唑N,O-缩醛和3-吡啶基-苯并噻唑6-氧羧酸两个系列共计300多个苯并噻唑类化合物，并对其除草活性和构效关系进行了系统研究，发现了3-吡啶基-苯并噻唑6-氧羧酸类化合物的除草活性。在此基础上进行多次结构优化，最终筛选到了1个高活性化合物—3-(3-氯-5-三氟甲基吡啶-2-基)苯并噻唑-2-酮-6-氧己酸甲酯（研发代号：NWAFU-J10）。在15g/ha剂量下，NWAFU-J10对婆婆纳、猪殃殃、麦家公、反枝苋、马齿苋、藜、播娘蒿、荠菜等数十种阔叶杂草的防效可达100%，同时，NWAFU-J10对小麦、水稻和玉米表现出很好的安全性。NWAFU-J10的除草活性与美国FMC公司开发的唑草酮相当，但生产成本大约仅为唑草酮的五分之一，具有极强的市场竞争力。NWAFU-J10具有全新的分子骨架、可望填补建国以来我国在除草剂核心活性骨架创制上的空白，具有极高的原始创新性和广阔的市场化前景。其次，课题组以N,N-二甲基甲酰胺二甲基缩醛和3-环丙基-3-氧代丙酸甲酯为起始原料，设计合成了53个N-酰基苄（或苯）胺异噁唑衍生物，并对其除草活性、构效关系及作用机制进行了系统研究，发现了一类新型的双作用机制除草剂先导化合物。其三，课题组设计合成了400多个苯（吡啶）甲酰胺衍生物，并对其除草活性，构效关系和作用机制进行了系统研究，研究结果该类化合物的作用靶标位于质体醌/类胡萝卜素生物合成途径，且与现有已知除草剂靶标不同，可能为一种新型除草剂作用靶标，相关工作仍在进一步研究中。