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 aspartate-semialdehyde 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 pK(a) values supports the theory that binding at the phosphate binding site is optimised for singly ionised phosphate analogues.
Cox
Russell J
RJ
School of Chemistry, University of Bristol, Cantock's Close, Clifton, Bristol BS8 1AS, UK. r.j.cox@bris.ac.uk
Gibson
Jennifer S
JS
Mayo Martín
María Belén
MB
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D001223:Aspartate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D007700:Kinetics; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000577:Amides; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010756:Phosphoric Acids; C032197:beta-aspartyl phosphate; D001224:Aspartic Acid; C011067:phosphoramidic acid; D001223:Aspartate-Semialdehyde Dehydrogenase