N-Heterocyclic sulfonamides and sultams as inhibitors of the bacterial enzyme diaminopimelate desuccinylase (DapE).
Diaminopimelate desuccinylase (DapE) is a promising antibacterial target involved in lysine biosynthesis and bacterial cell wall formation. Previously, N-aryl sulfonamide hit 1 (IC₅₀ = 72.9 μM) was optimized to 2 with enhanced potency (IC₅₀ = 8.9 ± 5.0 μM, Kᵢ = 1.36 ± 0.61 μM). In this paper we describe the synthesis of N-heterocyclic sulfonamides and N-aryl sultams to explore the effects of heterocycles and conformational constraints on DapE inhibition. Aminopyridine substitutions generally reduced activity, although N-pyridyl sulfonamide 6e retained moderate inhibition (68.5% at 100 μM). Five- and seven-membered sultams showed modest activity, with p-methoxybenzene 7b displaying the highest inhibition (60.4% at 100 μM). Docking studies predicted favorable zinc-binding for several analogues, particularly those with carboxylic acids, but these interactions generally did not improve experimental potency.