Enhancing Selectivity and Potency of S_NAr Covalent Inhibitors of NADPH Oxidase Enzymes

Dysregulated reactive oxygen species (ROS) are implicated in various diseases, positioning NADPH oxidase enzymes (NOXs) as attractive therapeutic targets. However, progress in tool compound discovery has been hindered by rational optimization strategies that can improve isoform selectivity. Starting from a nonselective but well-behaved NOX inhibitor (VAS2870), we have discovered a first-in-class NOX5 selective inhibitor through minor functionalization on a benzoxazolethiol moiety, which is released upon covalent modification to the target enzyme. These unexpected findings showcase a unique strategy for optimizing S_NAr covalent inhibitors and offer new avenues for the development of isoform-selective NOX inhibitors.