RESUMEN
Facile synthetic procedures and broad spectrum of biological activities are special attributes of sulfonamides. Sulfonamide derivatives have demonstrated potential as a class of compounds for the treatment of Alzheimer's disease (AD). Recent sulfonamide derivatives have been reported as prospective anti-AD agents, with a focus on analogues that significantly inhibit the function of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and exhibit remarkable antioxidant and anti-inflammatory properties, all of which are critical for the treatment of AD. Sulfonamide- mediated activation of nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the endogenous antioxidant response, has also been suggested as a potential therapeutic approach in AD. Additionally, it has been discovered that a number of sulfonamide derivatives show selectivity for the ß- and γ-secretase enzymes and a significant reduction of amyloid B (Aß) aggregation, which have been implicated in AD. The comparative molecular docking of benzenesulfonamide and donepezil, an AD reference drug showed comparable anti-AD activities. These suggest that sulfonamide derivatives may represent a new class of drugs for the treatment of AD. Thus, the current review will focus on recent studies on the chemical synthesis and evaluation of the anti-AD properties, molecular docking, pharmacological profile, and structure-activity relationship (SAR) of sulfonamide derivatives, as well as their potential anti-AD mechanisms of action. This paper offers a thorough assessment of the state of the art in this field of study and emphasizes the potential of sulfonamide derivatives synthesized during the 2012-2023 period as a new class of compounds for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Sulfonamidas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Sulfonamidas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/química , Humanos , Animales , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular/métodos , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/uso terapéutico , Antioxidantes/químicaRESUMEN
The surge of scientific interest in the discovery of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (NRF2)-activating molecules underscores the importance of NRF2 as a therapeutic target especially for oxidative stress. The chemical reactivity and biological activities of several bioactive compounds have been linked to the presence of α,ß-unsaturated structural systems. The α,ß-unsaturated carbonyl, sulfonyl and sulfinyl functional groups are reportedly the major α,ß-unsaturated moieties involved in the activation of the NRF2 signaling pathway. The carbonyl, sulfonyl and sulfinyl groups are generally electron-withdrawing groups, and the presence of the α,ß-unsaturated structure qualifies them as suitable electrophiles for Michael addition reaction with nucleophilic thiols of cysteine residues within the proximal negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1). The physicochemical property such as good lipophilicity of these moieties is also an advantage because it ensures solubility and membrane permeability required for the activation of the cytosolic NRF2/KEAP1 system. This review provides an overview of the reaction mechanism of α,ß-unsaturated moiety-bearing compounds with the NRF2/KEAP1 complex, their pharmacological properties, structural activity-relationship and their effect on antioxidant and anti-inflammatory responses. As the first of its kind, this review article offers collective and comprehensive information on NRF2-activators containing α,ß-unsaturated moiety with the aim of broadening their therapeutic prospects in a wide range of oxidative stress-related diseases.
Asunto(s)
Antioxidantes , Factor 2 Relacionado con NF-E2 , Antioxidantes/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Transducción de SeñalRESUMEN
Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling has become a key pathway for cellular regulation against oxidative stress and inflammation, and therefore an attractive therapeutic target. Several organosulfur compounds are reportedly activators of the Nrf2 pathway. Organosulfur compounds constitute an important class of therapeutic agents in medicinal chemistry due to their ability to participate in biosynthesis, metabolism, cellular functions, and protection of cells from oxidative damage. Sulfur has distinctive chemical properties such as a large number of oxidation states and versatility of reactions that promote fundamental biological reactions and redox biochemistry. The presence of sulfur is responsible for the peculiar features of organosulfur compounds which have been utilized against oxidative stress-mediated diseases. Nrf2 activation being a key therapeutic strategy for oxidative stress is closely tied to sulfur-based chemistry since the ability of compounds to react with sulfhydryl (-SH) groups is a common property of Nrf2 inducers. Although some individual organosulfur compounds have been reported as Nrf2 activators, there are no papers with a collective analysis of these Nrf2-activating organosulfur compounds which may help to broaden the knowledge of their therapeutic potentials and motivate further research. In line with this fact, for the first time, this review article provides collective and comprehensive information on Nrf2-activating organosulfur compounds and their therapeutic effects against oxidative stress, thereby enriching the chemical and pharmacological diversity of Nrf2 activators.
RESUMEN
Introduction:Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a key role in diverse gene expressions responsible for protection against oxidative stress and xenobiotics. Chalcones with a common chemical scaffold of 1,3-diaryl-2- propen-1-one, are abundantly present in nature with a wide variety of pharmacological properties. This review will discuss the interactions of natural and synthetic chalcones with Nrf2 signaling.Areas covered:Chalcones are reportedly found to activate Nrf2 signaling pathway, expression of Nrf2-regulated antioxidant genes, induce cytoprotective proteins and upregulate multidrug resistance-associated proteins. Chalcones being soft electrophiles are less prone to hostile off-target effects and unlikely to induce carcinogenicity and mutagenicity. Furthermore, their low toxicity, structural diversity, feasibility in structural reorganization and the presence of α,ß-unsaturated carbonyl group which makes them suitable drug candidates targeting Nrf2-dependent diseases.Expert opinion:Nrf2-Keap1 signaling pathway plays a central role in redox signaling. However, available therapeutic agents for Nrf2 activation have limited practical applications due to their associated risks, relatively low efficacy and bioavailability. The designing and fabrication of new chemical entities with chalcone scaffold-based Michael acceptor mechanism should be aimed as potential therapeutic Nrf2 activators to target oxidative stress and inflammation-mediated diseases such as atherosclerosis, Parkinson's disease and many more.