N-aryl sulfonamide inhibitors of the bacterial enzyme diaminopimelate desuccinylase (DapE) as potential new antibiotics

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, Ki = 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 Ki. Molecular docking studies provided insights into this enhanced activity, revealing key interactions within the DapE active site.