Switching Futile para‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition,Electrocatalysis, and Quantification

Understanding the correlation between structural features of small‐molecule drugs and their mode of action is a fascinating topic and crucial for the drug‐discovery process. However, in many cases, knowledge of the exact parameters that dictate the mode of action is still lacking. Following a large screening for ubiquitin specific protease 2 (USP2) inhibition, an effective para‐quinone‐based inhibitor with an unclear mode of action was identified. To gain a deeper understanding of the mechanism of inhibition, a set of para‐quinones were prepared and studied for USP2 inhibition, electrocatalysis, and reactive oxygen species (ROS) quantification. The excellent correlation obtained from the above‐mentioned studies disclosed a distinct pattern of “N?C=O?N” in the bicyclic para‐quinones to be a crucial factor for ROS generation, and demonstrated that minor changes in such a skeleton drastically altered the ROS‐generating ability. The knowledge acquired herein would serve as an important guideline for future medicinal chemistry optimization of related structures to select the preferred mode of action.