Sulfonamide a Valid Scaffold for Antioxidant Drug Development

Sulfonamides, like the well-known sulfa drugs, are ascribed to a myriad of biological activities, including antioxidant activity. In fact, several tertiary sulfonamides particularly N,N-disubstituted analogues are recognized as antioxidants being able to prevent or minimize oxidative damage that is associated in several oxidative-stress related diseases. The structural diversity of this class of compounds paved the way for drug discovery programs aimed to find therapeutic agents. Attributes such as low-cost synthetic procedures, easy accessibility of reagents and a broad spectrum of biological activities made sulfonamides and derivatives excellent runners for the synthesis of chemical libraries with structural diversity. Sulfonamide-based drugs are the majority of sulfur-containing drugs approved by the United States Food and Drug Administration (FDA). Although sulfonamide derivatives have been extensively exploited as antibacterial agents, their therapeutic potential as antioxidants is relatively underexplored despite the prevalence of oxidative stress-mediated diseases and the urgent need for new and more effective antioxidant drugs. Some sulfonamide derivatives were shown to activate the nuclear factor erythroid 2-related factor 2 (Nrf2), the main regulator of endogenous antioxidant response, a critical process used by cells as response to oxidative stress. The antioxidant role of sulfonamides and derivatives as Nrf2 activators is also reviewed. The antioxidant mechanism of action of sulfonamides has not been fully clarified but as they have antioxidant properties, it is a subject worthy of in-depth study. The present review is focused on sulfonamides and derivatives as potential antioxidants along the period 2013-2021 and intends to stimulate research in the area.