Unprotected primary sulfonamide group facilitates ring-forming cascade en route to polycyclic [1,4]oxazepine-based carbonic anhydrase inhibitors

Abstract

4-Chloro-3-nitrobenzenesulfonamide reacted cleanly at room-temperature with a range of bis-electrophilic phenols bearing an NH-acidic functionality (secondary carboxamide or pyrazole) in the ortho-position. This produced a novel class of [1,4]oxazepine-based primary sulfonamides which exhibited strong inhibition of therapeutically relevant human carbonic anhydrases. 2-Chloronitrobenzene did not enter a similar cyclocondensation process, even under prolonged heating. Thus, the primary sulfonamide functionality plays a dual role by enabling the [1,4]oxazepine ring construction and acting as a enzyme prosthetic zinc-binding group when the resulting [1,4]oxazepine sulfonamides are employed as carbonic anhydrase inhibitors.

Keywords: Carbonic anhydrase inhibitors; Electron-withdrawing group; Isoform-selectivity; Nucleophilic aromatic substitution; Primary sulfonamide; Reactivity-matched substrates; SMILES rearrangement.