Smart Bioisosteres: Beyond a spatial mimic to improved plant biology

生物电子等排体是开发新型农用化学品的重要替代设计选项，以保留或改善活性成分的整体生物学特性，如活性，生物活性和代谢稳定性。然而，迄今为止，连接基团（不直接参与与蛋白质靶标的结合）的生物电子等排替代物的开发仅集中在其支架特性上，以模拟拓扑结构，而忽略了对直接连接到支架的取代基的特性的影响（例如pKa或H-键合电位，杂交）。在开发新的农用化学品时，这些取代基特征对化合物的进展至关重要，特别是达到相关活性位点的潜力。该项目将设计、合成和评估邻位取代苯基衍生物的新生物电子等排体，目前还没有确定的替代方案。使用设计的支架，将制备一系列“匹配的分子对”，以系统地检查化合物作为一个整体的物理化学和ADME性质的变化（logP，溶解度，代谢稳定性），以及支架上关键功能取代基的特定变化，为这些材料提供新的见解。多孔支架将被并入已知的农用化学化合物中，对于该提议，已经确定了3种除草剂。将制备所设计的生物电子等排化合物，并研究其生物反应（从体外酶测定到温室中的全植物研究、对接和X射线研究、物理/代谢稳定性），并与含邻苯基的化合物进行比较。这些研究将为开发新的农用化学品提供新的认识和新的设计方案。

Bioisosteres are essential alternative design options in the development of new agrochemicals, to retain or improve overall biological properties of an active ingredient, such as activity, biokinetics, and metabolic stability. However, the development of bioisosteric replacements for linking groups (not directly involved in binding to the protein target) has to date focused exclusively on their scaffolding properties, to mimic topology, and neglected the effect on the properties of the substituents directly attached to the scaffold (e.g. pKa or H-bonding potential, hybridisation). In developing new agrochemicals, these substituent features are crucial to the progress of a compound, and notably the potential to reach the relevant site of activity. This project will design, synthesise and assess new bioisosteres for ortho-substituted phenyl derivatives, for which there are currently no established replacement options. With the designed scaffolds a series of 'matched molecular pairs' will be prepared, to examine systematically the change in the physicochemical and ADME properties of the compound as a whole (logP, solubility, metabolic stability), as well as the particular changes to the key functional substituents on the scaffold, providing new insights to these materials. Advantageous scaffolds will be incorporated into known agrochemical compounds, for which 3 herbicides have been identified for this proposal. The designed bioisosteric compound will be prepared and the biological response will be investigated (from in vitro enzyme assays, to whole plant studies in the glasshouse, docking and X-ray studies, physical / metabolic stability), and compared to that of the ortho-phenyl containing compounds. These studies will provide new understanding and new design options for the development of new agrochemicals.