Design, synthesis, and bioactivity of novel inhibitors of E. coli aspartate transcarbamoylase

A series of inhibitors of the aspartate transcarbamoylase, an enzyme involved in pyrimidine nucleotide biosynthesis, has been synthesized. These inhibitors are analogues of a highly potent inhibitor of this enzyme, N-phosphonacetyl-l-aspartate (PALA). Analogues have been synthesized with modifications at the α- and β-carboxylates as well as at the aspartate moiety. The ability of these compounds to inhibit the enzyme was evaluated. These studies, with functional group modified PALA derivatives, showed that amide groups can be a useful substitute of the carboxylate in order to reduce the charge on the molecule, and indicate that the relative position of the functional group in the β-position is more critical than the nature of the functional group. Some of the molecules synthesized here are potent inhibitors of the enzyme.

Graphical abstractA series of novel PALA derivatives were synthesized and ability to inhibit aspartate transcarbamoylase was determined.Figure optionsDownload full-size imageDownload as PowerPoint slide