A series of N -aryl sulfonamides was designed, synthesized, and evaluated for their ability to inhibit the bacterial enzyme N -succinyl-L,L-diaminopimelic acid desuccinylase (DapE, EC 3.5.1.18). Our initial lead compound, N -( o -methoxyphenyl)-toluenesulfonamide ( 4a ), identified through a high-throughput screen, showed modest inhibition, with an IC₅₀ of 72.9 μM. Through lead optimization, we improved the potency by modifying key functional groups. Replacing the o -OCH₃ on the aniline ring and p -CH₃ on the sulfonamide ring with p -CF₃ and p -OCH₃, respectively, while retaining the N -CHF₂ hydrophobic moiety, led to our most potent inhibitor, compound 4g (IC₅₀ = 8.9 ± 5.0 μM, K i = 1.36 ± 0.61 μM), representing an 8-fold increase in potency over hit 4a , and providing the most potent DapE inhibitor yet reported based on the K i. Molecular docking studies provided insights into this enhanced activity, revealing key interactions within the DapE active site. • 28 Analogs from HITS sulfonamide 4a IC₅₀ of 72.9 μM with DapE ninhydrin assay. • Most potent vs. DapE 4g (IC₅₀ = 8.9 ± 5.0 μM, Ki = 1.36 ± 0.61 μM) 8× over hit. • NmDapE X-ray PDB 5UEJ dock hit binds to single Zn 2+ sulfonamide oxygen. • Most potent 4g bidentate to both Zn 2+ plus N H of Thr326 to π-system. • Sulfonamide 4g is most potent DapE inhibitor ever reported based on Ki = 1.36 μM.
Flieger et al. (Sun,) studied this question.