Sulfonamide a Valid Scaffold for Antioxidant Drug Development

Abstract

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.

The Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects

“…Sulfonamide derivatives have been found to activate Nrf2 and inhibit Keap1-Nrf2 protein-protein interaction thereby antagonizing oxidative stress. This results in the elimination of reactive oxygen species (ROS), alteration of glutathione homeostasis, up-regulation of the expression of antioxidant response element dependent genes and enhancement of antioxidant defence mechanism [ 1 , 109 , 110 ]. Peng and co-workers [ 111 ] reported that caffeic acid sulfonamide derivatives ( 8 , 9 , 10 ) ( Table 1 ), when used in the treatment of H 2 O 2 -stimulated A549 cells, enhance mRNA expression of Nrf2 and its target genes.…”

An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects

“…Indeed, NRF2 regulates the expression of several antioxidant enzymes such as NAD(P)H Quinone Dehydrogenase 1 (NQO1) and heme oxygenase-1 (HO-1), which are involved in xenobiotic metabolism [ 57 ], in metabolism of carbohydrates [ 58 ], lipids and iron [ 59 ], and modulates anti-inflammatory responses [ 48 ]. In vitro and transgenic model systems, as well as clinical and epidemiological studies have implicated NRF2 activity on the activation of endogenous antioxidant and cytoprotective mechanisms in the prevention and treatment of oxidative stress and inflammation-mediated diseases, including neurodegenerative diseases, cardiovascular disorders, autoimmune diseases, and lung, liver and kidney chronic diseases [ 7 , 8 , 9 , 60 , 61 ]. A large body of data consider it a paradox that NRF2 inhibits tumor initiation and cancer metastasis via the elimination of ROS and carcinogens but becomes an accomplice in helping tumor cells to withstand high level of ROS and resist apoptosis which can be referred to as the reverse side of the NRF2/KEAP1 signaling pathway.…”

Thiosuccinimide enabled S–N bond formation to access N-sulfenylated sulfonamide derivatives with synthetic diversity

“…Since the landmark discovery of prontosil, sulfonamides, the compounds derived from 4-aminobenzenesulfonamide (sulfanilamide), have long been associated with medicine and agriculture due to their broad-spectrum antimicrobial activity and inexpensive nature. 1 Conventional structure–activity relationship studies believed that the free amino group at the phenylic para -position is essential for their antibacterial action, which can be attributed to the requirement of this substituent for sulfonamides to mimic p -aminobenzoic acid (PABA) for inhibiting folic acid biosynthesis. 2 Nevertheless, with the deepening of the investigation on the structural modification of sulfa drugs, it is found that the introduction of appropriate functional groups on the phenylamino group of sulfanilamide not only could improve its antibacterial performance but is also expected to produce new pharmacological activity.…”