Beyond Radical Scavengers: Focus on NADPH Oxidases (NOX) Inhibitors as New Agents for Antioxidant Therapy in Alzheimer’s Disease

Over the past decade, oxidative stress and neuroinflammation have been increasingly recognized as part of the pathology of Alzheimer's disease (AD). This observation has led to extensive efforts and attempts to apply antioxidant compounds as therapeutic agents for AD and other pathologies. However, most, if not all, of these attempts have failed in preclinical or clinical trials. A tentative explanation for this failure is radical scavengers' intrinsic lack of specificity in either their mode or district of action. The lack of specificity has been thought by some to be a source of so-called "reductive stress", another form of redox imbalance that might be just as toxic as oxidative stress. Thus, research interest is shifting from developing simple radical scavengers to designing and refining compounds targeting the overproduction of Reactive Oxygen Species (ROS) in specific pathological conditions. This can be achieved, for instance, by targeting the enzymes that are mainly responsible for their production, namely NADPH oxidases (NOX). In this review, we will discuss, from the point of view of medicinal chemistry, the main innovations in the development of NOX inhibitors and their potential employment for AD therapy. We will also discuss the experimental hurdles that slow down research in this field and possible solutions.