Synthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme -Succinyl-l,l-2,6-Diaminopimelic Acid Desuccinylase (DapE) as Potential Antibiotics.

Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of -succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from (DapE). The most potent pyrazole analog bears an aminopyridine amide with an IC of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog has an IC of 18.8 µM, with potency residing in the ()-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor with T = 50.2 °C and a K of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions.