Aspartyl Phosphonates and Phosphoramidates: The First Synthetic Inhibitors of Bacterial Aspartate-Semialdehyde Dehydrogenase

The synthesis of methylene phosphonate, difluoromethylene phosphonate and phosphoramidate analogues of aspartyl phosphate, together with reduced analogues, is described. These compounds were shown to be effective inhibitors of aspartatesemialdehyde dehydrogenase (ASA-DH) from Escherichia coli. However, despite the structural similarity of the compounds, different patterns of inhibition were observed, indicative of two phases of recognition and binding. Correlation between measured inhibition constants with pKa values supports the theory that binding at the phosphate binding site is optimised for singly ionised phosphate analogues.