Pyridine and piperidine derivatives as inhibitors of dihydrodipicolinic acid synthase, a key enzyme in the diaminopimelate pathway to l-lysine

Abstract

A key step in the diaminopimelate (DAP) pathway to L-lysine (7) involves condensation of pyruvate with aspartic acid β-semialdehyde (1) to yield L-2,3-dihydrodipicolinic acid (2) (DHDPA) catalyzed by DHDPA synthase. The best inhibitors of DHDPA synthase of the thirty pyridine and piperidine derivatives prepared were the N-oxide (15) of dipicolinic acid and the di-imidate (13) of dimethyl pyridine-2,6-dicarboxylate each with an IC50 value of 0.2 mM. The N-oxide (15) and dinitrile (12) are noncompetitive inhibitors with Ki values of 0.29 and 1.25 mM against aspartate semialdehyde and 0.06 and 0.34 mM against pyruvate, respectively.