The synthesis of N-heterocyclic sulfonamides and N-aryl sultams is described to explore the effects of heterocycles and conformational constraints on DapE inhibition to explore the effects of heterocycles and conformational constraints on DapE inhibition.
Abstract
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.
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