Synthesis and in vitro enzyme activity of aza, oxa and thia derivatives of bacterial cell wall biosynthesis intermediates

Mechanism based inhibitors of diaminopimelate aminotransferase (DAP-AT) were designed using knowledge of its substrate specificity and mechanism. Synthesis of thiolester and amide substrate analogues was achieved prior to in vitro inhibition studies, but ester analogues proved too unstable to isolate. Thia substrate analogues showed no inhibitory properties, but the aza substrate analogue 12a showed reversible inhibition vs. DAP-AT and time dependent inhibition in the absence of the natural substrate 4. Substrate analogue 12a is the first example of an amide inhibitor of PLP dependent enzymes. Antibiotic properties of 12a were also briefly assessed.