Synthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme N-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 <i>N</i>-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from <i>Haemophilus influenzae</i> (<i>Hi</i>DapE). The most potent pyrazole analog <b>7d</b> bears an aminopyridine amide with an IC₅₀ of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog <b>7q</b> has an IC₅₀ of 18.8 µM, with potency residing in the (<i>R</i>)-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor <b>(R)-7q</b> with T_m = 50.2 °C and a K_i of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions.