NRF2 Activation by Nitrogen Heterocycles: A Review

Abstract

Several nitrogen heterocyclic analogues have been applied to clinical practice, and about 75% of drugs approved by the FDA contain at least a heterocyclic moiety. Thus, nitrogen heterocycles are beneficial scaffolds that occupy a central position in the development of new drugs. The fact that certain nitrogen heterocyclic compounds significantly activate the NRF2/ARE signaling pathway and upregulate the expression of NRF2-dependent genes, especially HO-1 and NQO1, underscores the need to study the roles and pharmacological effects of N-based heterocyclic moieties in NRF2 activation. Furthermore, nitrogen heterocycles exhibit significant antioxidant and anti-inflammatory activities. NRF2-activating molecules have been of tremendous research interest in recent times due to their therapeutic roles in neuroinflammation and oxidative stress-mediated diseases. A comprehensive review of the NRF2-inducing activities of N-based heterocycles and their derivatives will broaden their therapeutic prospects in a wide range of diseases. Thus, the present review, as the first of its kind, provides an overview of the roles and effects of nitrogen heterocyclic moieties in the activation of the NRF2 signaling pathway underpinning their antioxidant and anti-inflammatory actions in several diseases, their pharmacological properties and structural–activity relationship are also discussed with the aim of making new discoveries that will stimulate innovative research in this area.

Facile synthesis of substituted 2-aroylbenzo[b]thiophen-3-ols to form novel triazole hybrids using click chemistry

“…This notion is supported by the fact that a large number of the USA Food and Drug Administration (FDA)-approved drugs contain one or several heterocyclic rings in their structures. 1–3 Therefore, access to a chemical library of small molecules containing one or more “privileged” heterocyclic rings is generally considered a prerequisite for effective drug discovery endeavors. 4,5 Among them, sulfur-containing heterocycles are gaining attention in organic synthesis due to their applications in materials sciences, pharmaceutical industries, and food chemistry.…”

An insight into role of amino acids as antioxidants via NRF2 activation

“…Over the years, oxidative stress has been shown to play a significant role in the pathogenesis of several diseases through pro-oxidant factors altering several enzymes, cellular structures, gene expression, and mitochondrial physiology (Egbujor et al 2020b , 2023a ). Numerous studies have indicated that KEAP1 has an intracellular sensing ability to act as a homodimer on the cell’s redox status in modulating the biological functions of the transcription factor NRF2 (Suzuki and Yamamoto 2015 ; Egbujor et al 2023b ). (Cuadrado et al 2018 ) reported that NRF2 is a molecular target for protein–protein interaction within the cell for cytoprotective ability.…”

“…(Chen et al 2015 ) revealed that in the endothelial cell, NRF2–KEAP1 signaling plays a significant role in modulating the redox homeostasis, thus preventing several cardio-metabolic diseases like atherosclerosis, hypertension, aging, and ischemia, through combination with antioxidant response elements (ARE) and subsequently promoting several antioxidant genes transcription. During oxidative stress or inflammation, NRF2 dissociates from KEAP1, resulting in nuclear transcription processes (Egbujor et al 2023b ). (Yamamoto et al 2018 ) described the NRF2–KEAP1 system as a thiol-based biosensor regulating redox status in the cell.…”

Efficient Synthesis of Highly Substituted N‐Arylamino quinolone‐based Pyrrolo[3,4‐b]pyridines and Pyrazolone‐based Pyrrolo[3,4‐b]pyridines Through a One‐Pot Three‐Component Reaction

“…These heterocycles are widely recognized to be helpful for various applications, including drugs, therapeutic agents, fungicides, and agrochemicals, as well as for advanced materials [1] . The most common in biology and medicine are pyrrolidine, pyrroline, pyrazoles, quinoline, imidazoles, and pyrimidine derivatives [2] …”

“…[1] The most common in biology and medicine are pyrrolidine, pyrroline, pyrazoles, quinoline, imidazoles, and pyrimidine derivatives. [2] From the literature, we realized that organic compounds containing quinoline [3] cores, pyrazoles, [4] and pyrrole-fused Nheterocyclic structural units, [5] whether free or fused with other heterocycles is an active pharmacophore in many biologically important molecules including anti-inflammatory, antimalarial, antifungal, cardiac, antihelmintic, anticonvulsant, antibacterial, and pain-reducing properties. Some representative drugs having quinoline, pyrazoles, and pyrrolopyridines with biological and photophysical properties are shown in Figure 1.…”