Nitrogen Heterocycles and NRF2 Activation

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Melford Chuka Egbujor	--	3232	2023-04-27 11:03:04	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	3232	2023-04-28 02:50:23	\|

This entry is adapted from the peer-reviewed paper 10.3390/molecules28062751

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 due to their therapeutic roles in neuroinflammation and oxidative stress-mediated diseases.

nitrogen heterocycles antioxidant anti-inflammatory neurodegenerative diseases NRF2

1. Introduction

Nitrogen-based heterocyclic compounds constitute an important class of heterocycles in drug discovery due to their vast medicinal applications. It is well established that nitrogen heterocyclic scaffolds are often present as common cores in a variety of pharmaceutical products. This implies that nitrogen heterocycles play essential roles in modern drug design and discovery. Currently, over 85% of all biologically active compounds are heterocycles or contain at least a heterocyclic moiety, and most frequently, nitrogen heterocycles function as the backbones of these complex structures ^[1].

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play essential physiological roles at moderate concentrations. However, when there is a disequilibrium between the rate of production of ROS and the rate at which antioxidant defenses neutralize them, oxidative stress occurs and results in oxidative damage and cell death ^[2]^[3]. Fortunately, some essential antioxidant molecules and detoxifying enzymes have been developed by cells as adequate defenses against oxidative stress. NRF2 protein is a notable antioxidant molecule that regulates cellular redox homeostasis; thus, its activation represents an effective antioxidant strategy against electrophilic and oxidative stress ^[4].

Consequently, NRF2-related pathways have become important therapeutic targets in drug discovery for inflammation and oxidative stress-mediated diseases ^[5]^[6]. The NRF2/KEAP1 signaling pathway modulates the antioxidant and cytoprotective responses of an organism to a great extent ^[4]. NRF2 is a transcription factor that is made up of about 605 amino acids and 7 functional domains known as Neh1-Neh7. The Neh1 domain is composed of a cap “n” collar basic region and the leucine zipper domain, which enables DNA binding and a nuclear localization signal that accounts for NRF2 nuclear translocation ^[7]^[8]. The Neh2 domain is responsible for NRF2 stability and its ubiquitination by KEAP1, while the Neh 3–5 domains facilitate NRF2 interaction with several coactivators ^[9]^[10]^[11]^[12]. The Neh6 domain binds to a β-transducin repeat-containing protein (β–TrCP), through which it enhances NRF2 ubiquitination, while the Neh7 domain enables NRF2 to bind to the retinoic X receptor and causes the inhibition of the NRF2–ARE pathway ^[13]^[14].

2. Nitrogen Heterocycles as Modulators of the NRF2 Pathway

The tendency of the nitrogen atom to readily form hydrogen bonding and various weak interactions with biological targets has distinguished N-based heterocyclic scaffolds as building blocks for a couple of drug candidates and expanded their utility in several therapeutic applications. The nitrogen atom of nitrogen heterocycle has a lone pair of electrons, which act as a hydrogen bond acceptor, resulting in the formation of a hydrogen bond (hydrogen atom bonded to an electronegative atom) network which enhances the stability of the nitrogen heterocycle and its interactions with diverse biological molecules ^[15]^[16]^[17]. Thus, both saturated and unsaturated N-based heterocycles are bioactive molecules of utmost medicinal importance.

2.1. Five-Membered Nitrogen Heterocycles and NRF2 Activation

Five-membered heterocyclic rings are commonly found in pharmaceuticals. It can be stipulated that their chemical structures permit variable interactions with essential biomolecules, hence their predominance in pharmaceuticals. Five membered nitrogen heterocycles such as pyrrole, imidazoles, pyrazoles and many more are components of the best-selling heterocyclic pharmaceuticals ^[18]. Currently, the pyrrole derivative, 3-carboxylic acid pyrroles have been patented as active NRF2 regulators (US2020/0031820A1).

2.1.1. Pyrrolidine/Pyrroline Analogues

Recent synthetic methods for pyrrolidines have been reviewed by ^[19]. A pyrrolidine derivative known as pyrrolidine dithiocarbamate (1) (Table 1) has been reported as a potent inducer of the NRF2 signaling pathway ^[20]. Pyrroline derivative (2) (Table 1) exerts protection against oxidative stress and hyperphosphorylation in neurodegenerative diseases via the activation of the NRF2–ARE pathway and upregulation of the expression of protein levels of HO-1 and NQO1 ^[21].

2.1.2. Pyrazoles

Pyrazoles are commonly prepared by reacting α,β-unsaturated aldehydes with hydrazine followed by dehydrogenation ^[22]. Several pyrazole analogues, such as arylcydohexyl pyrazoles (W02017060855A1), n-aryl pyrazoles (W02018109642) and biaryl pyrazoles (W02017060854) are already established NRF2 regulators. The antioxidant effect of pyrazoles has been linked to the activation of the NRF2/KEAP1 signaling pathway. Thus, pyrazole (3) (Table 1) induces oxidative damage in NRF2 knockout mice but not in wild-type mice due to compensative enhancement of NRF2-regulated antioxidant capacity.

Furthermore, pyrazole derivative (4) (Table 1) induces the NRF2 signaling pathway and inhibits glycogen synthase kinase-3β (GSK3β) ^[23]. The ability of compound 4 to activate NRF2 is ascribed to the presence of 2,4-dihydropyrano [2,3-c]pyrazole core, which also acts as a GSK3β inhibitor. Interestingly, the introduction of a pyrazole moiety to the curcumin scaffold improves the NRF2 activity and antioxidant capacity of curcumin. Evidently, the curcumin pyrazole derivative (5) (Table 1) has been found to exhibit better neuroprotective effects than curcumin and edaravone due to the pyrazole moiety ^[24].

2.1.3. Imidazolidine/Imidazole Analogues

The authors of ^[25] reported that a compound containing imidazolide, a conjugate base of IH-imidazole–CCDO-imidazolide (6) (Table 1) is 100 times more potent than DMF, a known NRF2 activator, in the activation of the NRF2 signaling pathway. Compound 6 is a synthetic oleanane triterpenoid containing an imidazole ring. It inhibits the production of nitric oxide and attenuates ROS generation in RAW264.7 cells; it also induces about 52 NRF2-target genes, including NQO1, and HO-1 via NRF2 activation. This type of NRF2 activation has also been linked to the amelioration of cardiac dysfunction and emphysema induced by cigarette smoke ^[26]. Furthermore, an imidazole analogue olmesartan (7) (Table 1) has been of therapeutic importance in hypertension.

2.1.4. Triazoles

Triazoles possess significant anti-inflammatory and antioxidant activities, and thus they have been extensively studied in neurodegenerative diseases ^[27]^[28]. The triazole derivatives (8 and 9) (Table 1) bearing 1,4-diaryl-1,2,3-triazole scaffolds significantly activate the NRF2 signaling pathway by inhibiting the KEAP1/NRF2 protein–protein interaction ^[29]. They also upregulate the expression levels of NRF2 dependent genes, including HO-1 and NQO1. 1,2,4-Triazole derivative (10) (Table 1) exerts a therapeutic effect in cerebral ischemic injury. It eliminates ROS, restores mitochondrial transmembrane potential, and attenuates neurological deficits in middle cerebral artery occlusion in acute ischemic stroke via NRF2 activation and induction of its antioxidant proteins such as HO-1, NQO1 and GCLC ^[30]. In a similar report, ^[31] reiterated that the neuroprotective effect of 1,2,4-triazole derivative (11) (Table 1) in cerebral ischemic injury is initiated by the antioxidant response element (ARE) and antioxidant genes HO-1 and NQO1 via the activation of the NRF2–ARE signaling pathway. Another 1,2,4-triazole analogue (12) (Table 1) with good bioavailability reportedly exhibited significant neuroprotective action against ischemic brain injury ^[32].

2.2. Six-Membered N-Heterocyclic Rings and NRF2 Activation

2.2.1. Piperidines

Piperidine exhibits antioxidant and anti-inflammatory activities and has been utilized as an essential scaffold in drug discovery ^[33]. A piperidine alkaloid (piperine) (13) (Table 1) protects neuronal cells against H₂O₂-induced ROS accumulation, apoptosis and oxidative damage via NRF2-dependent phase II antioxidant enzymes, especially HO-1 and NQO1 ^[34]. The authors of ^[35] reported that the cinnamyl piperidine analogue (14) (Table 1) inhibits neddylation, migration and increases apoptosis of gastric cancer cells via a process partly mediated by the NRF2–KEAP1 signaling pathway.

2.2.2. Pyridine Analogues

Pyridines possess antioxidant and anti-inflammatory properties ^[36]^[37]. Pyridine alkaloid (15) (Table 1) obtained from Fusarium lateritium enhances the expression of NRF2 and its target genes HO-1, and NQO1, thereby attenuating oxidative stress and apoptosis in glutamate-treated hippocampal HT22 cells ^[38]. This implies that the significant neuroprotective effects of pyridine can be attributed to its ability to activate the NRF2 signaling pathway. Pyridine derivative (16) (Table 1) also protects dopaminergic neurons from MPTP-induced oxidative stress; it suppresses the generation of proinflammatory enzymes and cytokines via the activation of NRF2 and upregulation of the mRNA levels of HO-1, SOD1, GCLM and GCLC, the NRF2-dependent antioxidant enzymes ^[39].

2.2.3. Pyrimidine and Pyrazine Analogues

A pyrimidine analogue 17 (Table 1) has been found to elevate the mRNA and protein levels of NRF2-target antioxidant enzymes such as HO-1, NQO1, GCLM and GCLC in BV-2 cells. Through NRF2 activation, it exerts anti-inflammatory, antioxidant and neuroprotective effects. In addition to the upregulation of HO-1 via the activation of NRF2/HO-1 signaling, compound 17 also activates AMPK/HO-1 signaling and through these processes, it effects neuroprotection of nigral neurons in Parkinson’s disease ^[40]. In a similar development, Lee and co-workers ^[41] further corroborated that pyrazolo[3,4-d]pyrimidine (18) (Table 1) protects nigral dopaminergic neurons and inhibits the dopamine deficiency-related motor deficits via NRF2 activation and upregulation of HO-1, NQO1, GCLM and GCLC. Another Pyrazolo[3,4-d]pyrimidine derivative (19) (Table 1) ameliorates hepatic ischemia reperfusion injury in mice by inhibiting p21-activated kinase 4 (PAK4) due to its ability to stabilize NRF2 and enhance antioxidant capacity in mice ^[42].

Pyrazine which belongs to the same diazine class as pyrimidine has two nitrogen atoms in the 1- and 4-positions of the ring. Tetramethyl pyrazine (20) (Table 1) exhibits a significant antioxidant and anti-apoptotic activity in MPTP-induced Parkinson’s disease in mice via the upregulation of the expression levels of NRF2, GCLC, Bax and Bcl-2 ^[43].

2.2.4. Triazines

Triazines exhibit antioxidant and anti-inflammatory activities ^[44]^[45]. Triazines also exert neuroprotective effects in neurodegenerative diseases. Triazine analogues (21 and 22) (Table 1) maintain redox homeostasis, improve cell survival and enhance the overall antioxidant responses in organisms via the activation of NRF2 and upregulation of GPx1, GCS, SOD and CAT in neuronal cells ^[46]. Similarly, 1,2,4-triazine (23) (Table 1) inhibits H₂O₂-induced cell death, and exerts a neuroprotective effect in neuron-like PC12 cells via the activation of NRF2 and induction of GCS, HO-1 and GPX ^[47].

Table 1. Five- and six-membered nitrogen heterocyclic compounds and NRF2-inducing activities.

S/N	Molecule/Structure	Effective concentration(s)	NRF2 Target Genes	Disease of Interest	Study Model	Biological Activity of Interest	Reference(s)
1	Pyrrolidine core Pyrrolidine-1-carbodithioic acid	20 mg/kg	HO-1, NQO1, GCLM, GCLC	AD, Oxidative stress	Mice, Astrocytes	Antioxidant	^[20]
		100 mg/kg		Infertility	Rats	Antioxidant, Anti-inflammatory	^[48]
		50 mg/kg	GPx1, GPx4	Inflammation bowel disease (IBD)	Mice	Antioxidant, Anti-inflammatory	^[49]
		100 µM	NQO1, GCLM	Oxidative stress	HepG2 Cells	GCL induction, NRF2 localization	^[50]
		1–10 µM	HO-1, NQO1, GCLM, GCLC	AD, Aβ toxicity	Mice	Antioxidant, neurogenesis	^[51]
2	Pyrroline core (Z)-Methyl-4-(3,4-dihydroxybenzylidene)-2-methyl-5-oxo-1-phenethyl-4,5-dihydro-1H-pyrrolin-3-carboxylate.	1 µM	HO-1, NQO1	Neurodegenerative diseases	SH-SY5Y Cells	Antioxidant	^[21]
3	Pyrazole core 1H-Pyrazole	150 mg/kg	HO-1, GST	Liver injury, Oxidative stress	Mice	Antioxidant	^[52]
3	Pyrazole core 1H-Pyrazole	150 mg/kg	HO-1	Oxidative stress	Mice	Antioxidant	^[53]
4	6-amino-3-methyl-4-(2-nitrophenyl) -2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile	0.3–30 µM	HO-1, NQO1	AD, Oxidative stress	AREc32 Cells	Antioxidant, Anti-inflammatory	^[23]
5	4-(3,5-bis((E)-4-hydroxy-3-methoxystyryl)-1H-pyrazol-1-yl)benzonitrile	1.25–5µM	GPx	Oxidative stress	PC12 Cells	Antioxidant	^[24]
6	Imidazole core (4aR,6aS,12aS,12bS,14bR)-8a-(1H-imidazole-1-carbonyl)-4,4,6a,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14b-icosahydropicene-2-carbonitrile	50–200 mg/kg	HO-1, NQO1	Lung cancer	Mice, RAW 264.7 Cells	Antioxidant, Anti-inflammatory	^[25]
		30 µmol/kg	HO-1, NQO1, GCLC	Acute Kidney Injury	Mice	Antioxidant, Anti-inflammatory	^[54]
		2 mg/kg	HO-1, NQO1, GCLC	Intestinal ischemia/reperfusion	Mice	Antioxidant, Anti-inflammatory	^[55]
7	1-((2’-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)methyl)-4-hydroxy-2-propyl-1H-imidazole-5-carboxylic acid	10 mg/kg	GPx	Chronic nephrotoxicity	Rats	Antioxidant, Anti-inflammatory	^[56]
8	Triazole core 4-(3-nitrophenyl)-1-(m-tolyl)-1H-1,2,3-triazole	10 µM	HO-1, NQO1	Oxidative stress	HEK293 Cells, FP and NQO1 Assay	Antioxidant	^[29]
9	1-(3-iodophenyl)-4-(3-nitrophenyl)-1H-1,2,3-triazole	10 µM	HO-1, NQO1	Oxidative stress	HEK293 Cells, FP and NQO1 Assay	Antioxidant	^[29]
10	2-(1-(3,5-dimethylphenyl)-5-(2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)phenol	<400 mg/kg	HO-1, NQO1	Ischemia stroke	Rats	Antioxidants	^[31]
11	2-(5-(2-hydroxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)phenol	<1000 mg/kg	HO-1, NQO1	Cerebral ischemic injury	Rats	Antioxidants	^[30]
12	4-(3-(2-hydroxy-4-methoxyphenyl)-5-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzenesulfonamide	2.5–10 µM	GPx, SOD	Ischemic stroke	PC12 Cells	Antioxidant	^[32]
13	Piperidine core (2E,4E)-5-(2-methoxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one	100 mg/kg	HO-1, NQO1	PD	PC12 Cells	Antioxiodant	^[34]
14	N-(4-pentylphenyl)-1-(3-phenylpropyl)piperidine-4-carboxamide		E1/E2/E2 enzymes	Gastric cancer	MIGC803 Cells	Anticancer	^[35]
15	Pyridine core (+)-4,6-Anhydrooxysporidinone	2.5 and 5 µM	HO-1	Oxidative stress, apoptosis	HT22 cells	Antioxidant	^[38]
16	(E)-3-chloro-2-(2-((2-chlorophenyl)sulfonyl)vinyl)pyridine	30 mg/kg	HO-1, GCLC, GCLM, SOD-1	PD	Mice	Antioxidant, anti-inflammatory	^[39]
17	Pyrimidine core 1-(tert-butyl)-6-methoxy-N-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine	30 mg/kg	HO-1, NQO1, GCLM,	PD	Mice	Antioxidant, anti-inflammatory	^[40]
18	1-benzyl-6-(methylthio)-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine	2000 mg/kg	HO-1, NQO1, GCLM, GCLC	PD	Mice	Antioxidant, anti-inflammatory	^[41]
19	1-((3-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)ethynyl)cyclohexanol	20 µM	HO-1, NQO1	Ischemia reperfusion injury	Mice	Antioxidant, anti-inflammatory	^[42]
20	Pyrazine core tetramethyl pyrazine	20 mg/kg	GCLC	PD	Mice	Antioxidant	^[43]
21	Triazine core 3-(methylthio)-5,6-diphenyl-1,2,4-triazine	10 µM	HO-1, GPx1	AD	PC12 Cells	Antioxidant	^[46]
22	5,6-bis(4-chlorophenyl)-3-(methylthio)-1,2,4-triazine	10 µM	HO-1, GPx1	AD	PC12 Cells	Antioxidant	^[46]
23	5,6-bis(4-methoxyphenyl)-3-(methylthio)-1,2,4-triazine	5–20 µ	HO-1, GPx1	AD	PC12 Cells	Antioxidant, anti-inflammatory	^[47]

2.3. Fused/Condensed Nitrogen Heterocyclic Compounds

2.3.1. Indoles

The synthesis of indoles has been reviewed by ^[57]. Indole-3-carbinol (I3C) (24) (Table 2), abundantly found in crucifers, regulates the NRF2 signaling pathway and exerts chemopreventive effects. The compound 24 induces ARE-luciferase activity and NRF2-mediated genes, and suppresses the incidence of palpable tumors and genitourinary weight ^[58]. Although compound 24 is effective in activating the NRF2 signaling pathway, available data indicate that its dimerization to 3,3-iindolylmethane (25) (Table 2) results in improved NRF2-inducing activity. In a comparative study of their potential NRF2-inducing activity in murine fibroblasts (NIH3T3), compound 25 was found to induce the transactivation of NRF2 and upregulation of NQO1, γGCS and HO-1 in contrast to its precursor (24) ^[59]. Prenylated indole alkaloid (26) (Table 2) also exerts neuroprotection against oxidative stress in SH-SY5Y cells via the nuclear translocation of NRF2 and the induction of NQO1 and HO-1. It activates NRF2 signaling by binding non-covalently with KEAP1, resulting in the reduction of ROS accumulation and the enhancement of the GSH level ^[60]. An indole analogue bearing a lactic acid moiety (27) (Table 2) attenuates inflammation and protects intestinal epithelial cells via the activation of NRF2 and aryl hydrogen receptor pathways ^[61]. Furthermore, an indole derivative (28) (Table 2) reduces ROS levels and improves neuronal viability in Parkinson’s disease via NRF2 activation ^[62]. It is important to note that several indole derivatives are non-covalent KEAP1-NRF2 protein–protein interaction (PPI) inhibitors. Through this mechanism, indole derivatives 29 and 30 (Table 2) increase the expression level of NQO1 and outperform tert-butylhydroquinone (tBHQ), a known NRF2 activator ^[63]^[64].

Table 2. Fused Nitrogen heterocyclic compounds and NRF2-inducing activities.

S/N	Molecule/Structure	Effective Concentration(s)	NRF2 Target Genes	Disease of Interest	Study Model	Biological Activity of Interest	Reference(s)
24	Indole core (1H-indol-3-yl)methanol	20mg/kg	NQO1	Prostate cancer	Mice	Antioxidant	^[58]
25	3,3′-diindolylmethane	25–100 µM	NQO1, HO-1	Oxidative stress	NIH3T3 Cells	Antioxidant	^[59]
25	3,3′-diindolylmethane	5 µM	NQO1	Prostate cancer	TRAMP mice, C1 Cells	Antioxidant, Anticancer	^[65]
26	(3R,6S,12aR,13aR)-3-isopropyl-12a-methoxy-13a-methyl-6-(2-methylprop-1-en-1-yl)-2,3,13,13a-tetrahydro-1H-pyrazino[1’,2’:3,4]pyrimido[1,6-a]indole-1,4,12(6H,12aH)-trione	10–50 µM	NQO1	Oxidative stress	SH-SY5Y Cells	Antioxidant	^[60]
27	2-hydroxy-3-(1H-indol-3-yl)propanoic acid	0.1–10 mM	NQO1, SOD-2, GPX-2	Intestinal inflammation	Gut epithelial cells	Antioxidant, Anti-inflammatory	^[61]
28	2,3-dihydrocyclopenta[b]indol-1(4H)-one	0.1 µM	NQO1	PD	SH-SY5Y	Antioxidant	^[62]
29	1-((4-methoxyphenyl)sulfonyl)-5-(((4-methoxyphenyl)sulfonyl)methyl)-2-methyl-N’-phenyl-1H-benzo[g]indole-3-carbohydrazide	4–100 µM	NQO1	Oxidative stress	MEF Cells, HepG2 Cells	Antioxidant	^[63]
30	5-(3-(((3-methoxybenzyl)amino)methyl)indolin-1-yl)thiophene-2-carboxylic acid	5 µM	NQO1	Oxidative stress	HeLa Cells	Antioxidant	^[64]
31	Quinazoline core 2-(4-bromophenyl)quinazolin-4(1H)-one	15, 30 mg/kg	NQO1, HO-1	Liver carcinogenesis	Rat	Antioxidant, Anticancer	^[66]
32	indolo[2,1-b]quinazoline-6,12-dione	1 µM	HO-1, GCLC	Oxidative stress	HepG2 Cells	Antioxidant	^[67]
33	Isoquinoline core (Z)-3-(2-(3-fluorophenyl)-2-oxoethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one	10 µM	NQO1	Oxidative stress	HepG2-ARE-C8 Cells	Antioxidant	^[68]
34	(Z)-3-(2-oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one	10 µM	NQO1	Oxidative stress	HepG2-ARE-C8 Cells	Antioxidant	^[68]
35	7-fluoro-1,3-diphenylisoquinolin-1-amine	10, 25 mg/kg	HO-1	Amnesia, Oxidative stress	Mice	Anti-amnesic, Antioxidant	^[69]
36	9,10-dimethoxy-5,6-dihydro-^[1]^[70]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium	50 mg/kg	NQO1, HO-1, SOD-1, CAT, GPx	Gouty arthritis	Rats	Antioxidant, anti-inflammatory	^[71]
37	2-(4-methoxy-N-(4-(4-methoxy-N-(2,2,2-trifluoroethyl)phenylsulfonamido)isoquinolin-1-yl)phenylsulfonamido)acetic acid	15 µM	NQO1	Hepatic injury	U2OS Cells	Antioxidant, Hepatocellular protection	^[72]^[73]

2.3.2. Quinazolines

Quinazoline is an aromatic fused N-heterocyclic compound containing a benzene and pyrimidine ring. They are biologically active, and are components of several pharmaceuticals, including notable drugs ^[74]. The quinazolinone derivative (31) (Table 2) upregulates the expression levels of NRF2, HO-1 and NQO1, with a consequent downregulation of the expression of KEAP1, AhR and CYP1B1 ^[66]. This modulation of the AhR/CYP1B1/NRF2/KEAP1 signaling pathway by compound 31 accounts for its chemotherapeutic potency in the inhibition of liver carcinogenesis. Tryptanthrin, a natural quinazoline derivative (32) (Table 2) obtained from Isatidis radix, has been found to upregulate the expression levels of NRF2 and its target genes. Compound 32 also exhibits hepatoprotective effects against oxidative stress via the activation of the extracellular signal regulated kinase (ERK)/NRF2 signaling pathway in HepG2 cells ^[67].

2.3.3. Isoquinolines

Compounds 33 and 34 activate the NRF2/ARE signaling pathway and elevate NQO1 at the cellular level ^[68]^[75]. Diphenyl isoquinoline-I-amine derivative (35) (Table 2) exhibits anti-amnesic activity which has been linked to its ability to activate the NRF2/HO-1 signaling pathway. Through this activation, it attenuates oxidative stress and cholinergic dysfunction in the prefrontal cortex of mice exposed to scopolamine ^[69]. Furthermore, isoquinoline alkaloid (36) (Table 2) upregulates the expression of NRF2 transcription factor and its target genes such as HO-1, GPX, SOD, CAT and NQO1, which help in alleviating monosodium urate crystal-induced inflammation in rats ^[71].

Isoquinoline PRL-295 (37) (Table 2) increases KEAP1 thermostability in cell lysates and causes a disruption of its interaction with NRF2 in single live cells. This leads to the activation of NRF2 and enhanced hepatocellular protection.

3. Structure–Activity Relationship of NRF2-Activating Nitrogen Heterocyclic Molecules

The SAR assessment of nitrogen heterocyclic molecules for improved NRF2-inducing activity is represented in Figure 1. The pyrrolidine moiety in compound 1 influences the antioxidant activity. The introduction of the pyrrolidine moiety to caffeic acid improves its antioxidant activity. The replacement of the OH of the COOH of caffeic acid with pyrrolidine increases its ability to attenuate lipid peroxidation and improve antioxidant capacity via the activation of Nrf2-dependent antioxidant enzyme HO-1 pathway and AKT pathway in heart ^[76]. The SAR studies of pyrazole derivatives indicate that the incorporation of the pyrazole core (3) increases their total antioxidant activity ^[77]. Although compound 6 activates the NRF2 signaling pathway and upregulates the expression levels of HO-1 and NQO1, the introduction of 2- and 3-pyridyl moieties to the imidazole produces better drug candidates 40 and 41, respectively ^[78]. For 1,4-diaryl-1,2,3-triazoles (8 and 9), the insertion of a nitro group at the meta position of the 4-phenyl ring and a nitro (42), methyl (43) or halogen group (44) at the meta position of the 1-phenyl ring are the best conformations required for NRF2 cell-based activity ^[29]. For 1,2,4-triazole derivatives 10, 11 and 12, ^[31] reported that the introduction of alkyl groups at the 3-position of the 1,2,4-triazole moiety enhanced the NRF2-mediated neuroprotective effects. Notably, the 3,5-dimethyl substitution (10) confers the best NRF2-inducing activity and neuroprotection. For piperidine derivatives 13 and 14, the introduction of N,N-dibutyl, N,N-dipropyl, N,N-bistrifluoromethyl or p-methyl to their piperidine scaffold enhances their pharmacological efficiency ^[79]. Compound 16 was designed based on SAR analysis, and it exhibits superlative NRF2-inducing activity. Among the drugs approved by the USA FDA, the pyridine moiety remains the second most commonly introduced aromatic N-heterocycle ^[80]^[81]. According to ^[82], the replacement of chlorobenzene with a pyridine ring and OMe with Cl- in vinyl sulfone (45: EC₅₀ = 530 nM) improves its NRF2-inducing activity (46: EC₅₀ = 0.618 µM). Furthermore, the insertion of 3-Cl into the pyridine ring of 46 confers the highest NRF2-inducing activity (16: EC₅₀ = 0.026 µM).

/media/item_content/202304/644b171b47811molecules-28-02751-g001.png

Figure 1. Structure–activity relationship (SAR) of NRF2-activating nitrogen heterocycle-containing molecules. The SAR assessment of molecules showed improved NRF2-inducing activity with the introduction of certain nitrogen heterocyclic compounds.

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