Smart Bioisosteres: Beyond a spatial mimic to improved plant biology

在开发新的农用化学品时，生物等位体是必要的替代设计选择，以保持或改善活性成分的整体生物学性质，如活性、生物动力学和代谢稳定性。然而，到目前为止，用于连接基团(不直接参与与蛋白质靶标结合)的生物等位取代物的开发仅集中在它们的支架性质上，以模拟拓扑结构，而忽略了对直接连接到支架上的取代基性质的影响(例如，PKA或氢键势能，杂化)。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，尤其是达到相关活性部位的可能性。该项目将为邻位取代苯衍生物设计、合成和评估新的生物等位体，目前还没有确定的替代选择。利用所设计的支架，将制备一系列匹配的分子对，以系统地检测化合物整体的物理化学和ADME性质(logP、溶解性、代谢稳定性)的变化，以及支架上关键功能取代基的特殊变化，为这些材料提供新的见解。有利的支架将被合并到已知的农用化合物中，对于这些化合物，本提议已确定了3种除草剂。将制备所设计的生物等位化合物，并将研究其生物响应(从体外酶分析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)，并与含有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理解和新的设计选择。

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.