Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

Abstract

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).

Keywords

• diaminopimelate desuccinylase
• DapE
• ninhydrin enzyme assay
• indoline
• sulfonamide
• enzyme inhibition