Smart Bioisosteres: Beyond a spatial mimic to improved plant biology

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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.