Next Article in Journal
A Novel Strategy for Automatic Mode Pairing on the Model Updating of Railway Systems with Nonproportional Damping
Next Article in Special Issue
An Update of Carbazole Treatment Strategies for COVID-19 Infection
Previous Article in Journal
Experiments and Fluent–Engineering Discrete Element Method-Based Numerical Analysis of Block Motion in Underwater Rock-Plug Blasting
Previous Article in Special Issue
A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Applied Sciences
Volume 13
Issue 1
10.3390/app13010349
applsci-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Carbazoles: Role and Functions in Fighting Diabetes

by
Fedora Grande
1,†,
Giuseppina Ioele
1,†,
Anna Caruso
1,2,*,
Maria Antonietta Occhiuzzi
1,
Hussein El-Kashef
3,
Carmela Saturnino
2 and
Maria Stefania Sinicropi
1
1
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
2
Department of Science, University of Basilicata, 85100 Potenza, Italy
3
Faculty of Science, Assiut University, Assiut 71516, Egypt
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Appl. Sci. 2023, 13(1), 349; https://doi.org/10.3390/app13010349
Submission received: 7 November 2022 / Revised: 20 December 2022 / Accepted: 22 December 2022 / Published: 27 December 2022
(This article belongs to the Special Issue Carbazole Derivatives: Latest Advances and Prospects)
Browse Figures
Versions Notes

Abstract

:
Carbazole derivatives have gained a lot of attention in medicinal chemistry over the last few decades due to their wide range of biological and pharmacological properties, including antibacterial, antitumor, antioxidant, and anti-inflammatory activities. The therapeutic potential of natural, semi-synthetic or synthetic carbazole-containing molecules has expanded considerably owing to their role in the pathogenesis and development of diabetes. Several studies have demonstrated the ability of carbazole derivatives to reduce oxidative stress, block adrenergic hyperactivation, prevent damage to pancreatic cells and modulate carbohydrate metabolism. In this survey, we summarize the latest advances in the synthetic and natural carbazole-containing compounds involved in diabetes pathways.

1. Introduction

The term “diabetes mellitus” (DM) refers to a group of chronic metabolic disorders characterized by hyperglycemia due to insufficient insulin secretion (type 1 DM) or to an inadequate response of the body to the action of this hormone (type 2 DM) [1]. Since a constant increase in glucose concentration in the blood can lead to serious consequences for several organs, including the eyes, kidneys, cardiovascular system, and central nervous system (CNS) [2,3] monitoring glycemia is of primary importance [4,5]
An effective approach to reduce postprandial blood glucose concentration is to inhibit the enzyme α-glucosidase, which catalyzes the final stage of the digestion process of carbohydrates to monosaccharides. These latter sugars are then absorbed and enter the bloodstream, thus increasing blood glucose levels [6]. The damages caused by hyperglycemia are related to the alteration of several physiological pathways. Several studies have shown, for example, that high levels of glucose, fatty acids, and insulin in the blood promote the production of reactive oxygen species (ROS), which cause direct DNA damage and promote insulin resistance [7].
Furthermore, by overstimulating the IGF-1 factor or by activating different kinase proteins, hyperglycemia favors cellular hyperproliferation and consequently the onset of cancer [8,9,10]. As a result of scientific advances, a wide range of anti-diabetic drugs are now available, improving the quality and length of life in type 2 diabetic patients.
These drugs, which belong to different chemical classes, can lower blood glucose levels through a variety of mechanisms (see Table 1 and Figure 1).
Metformin, one of the most commonly used oral hypoglycemic drugs, acts, for example, by increasing the utilization of glucose in peripheral tissues and by decreasing hepatic glucose production. Sulfonylureas, on the other hand, are able to modulate blood glucose levels by stimulating insulin secretion from pancreatic beta cells. Thiazolidinediones (TZDs) binds the peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor that regulates the expression of specific genes, and improves the sensitivity of fatty tissue, skeletal muscles and liver to insulin. More recently, new classes of drugs able to control hyperglycemia have been introduced. Among these, incretins, DPP-4 resistant GLP-1 analogs, and DPP-4 inhibitors play an important role; they are able to promote an increase in endogenous GLP-1 levels and stimulate pancreatic cells to release insulin. SGLT2 inhibitors increase glucose excretion in the urine by preventing glucose reabsorption in the renal tubules. Despite the therapeutic goals achieved by this diverse range of diabetes drugs, their clinical use is associated with undesirable side effects (summarized in Table 1), including dangerous hypoglycemic episodes [11]. Therefore, the identification of new molecules that preserve hypoglycemic activity while having reduced toxicity remains a goal of the scientific community. In this context, carbazole derivatives could represent valid therapeutic alternatives. Carbazole (I) (Figure 2) is a tricyclic heterocycle alkaloid consisting of two benzene rings fused on both sides of a pyrrole ring [12,13,14,15].
The first naturally occurring carbazole was isolated from Murraya koenigii Spreng. Murraya euchrestifolia has been found to be a rich source of carbazole alkaloids, providing a variety of novel structures. Some bioactive carbazole alkaloids have also been obtained from other sources such as actinomycetes, blue-green algae and mammalian systems [16,17].
A large number of studies reported in the literature were focused on the biological properties of carbazole and its derivatives, such as antimicrobial, anti-inflammatory, antitumor, antioxidant, antiepileptic, antihistamine, antidiarrheal, analgesic, neuroprotective, and inhibiting properties of pancreatic lipase [18,19,20,21].
In particular, some compounds belonging to this chemical class have shown promising activities in controlling glucose metabolism in hypertensive patients with type 2 DM and in improving insulin sensitivity [22]. In this review, we summarize the latest advances in the potential role of carbazole derivatives either in the prevention of or in the treatment of diabetes. Overall, the data herein reported could provide an important resource for the development of novel, efficient, and safe agents for innovative diabetes treatment.

2. Carbazole Derivatives in the Pathogenesis of Diabetes

Over the years, the academic community has delved into the chemical and pharmacological properties of small heterocyclic molecules, including those with a carbazole-based structure [23,24,25,26]. Growing interest in these derivatives has resulted in the development of various synthetic routes for their preparation as well as their extraction from various plants. Several carbazole-containing molecules have found application in the pharmaceutical field. In particular, the studies included in this review showed that certain derivatives are promising antidiabetic agents or may otherwise play an important role in the pathogenesis of diabetes. Data reported in the literature suggest that carbazoles are able to modulate glucose metabolism, block adrenergic hyperactivation, prevent damage to β cells of the pancreas, inhibit inflammatory and oxidative mediators, control the cryptochrome or inhibit α-glucosidase (Table 2). Therefore, carbazole represents a versatile scaffold for the preparation of biologically active derivatives, useful in the treatment of diabetes [6,7,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46].

2.1. Carvedilol

The carbazole derivative 1 (carvedilol, 1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol) (Figure 3), synthesized by the reaction of 4-(oxirane 2-ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy)ethylamine [47], was discovered in a study devoted to discovering agents useful in the treatment of congestive heart failure. The interaction of carvedilol (1) with beta-adrenergic receptors is stereospecific, in a similar way that was demonstrated for carazolol, a veterinary medicine drug used to reduce stress in animals during transport [48]. This optically active compound exhibits activity as a selective beta-adrenergic receptor blocker such as the S (−) enantiomer, whereas the R (+) enantiomer is capable of antagonizing both alpha-1 and beta-adrenergic receptors. These characteristics make this molecule more effective than other traditional beta-blockers in the treatment of heart failure and in the regulation of myocardial functions. Furthermore, unlike other beta-blockers, it does not cause alterations in the metabolism of carbohydrates and lipids [49].
Carvedilol (1) was found to reduce insulin resistance by increasing the sensitivity of insulin receptors (IRs) and by reducing the activity of the sympathetic nervous system [50]. The adrenergic system, in part through beta-2 adrenergic receptors, regulates glucose and lipid metabolism in the liver, adipose tissue, and skeletal muscle.
Taking into consideration all these properties, several studies were focused on the evaluation of the efficacy of carvedilol (1) in preventing heart complications in patients with diabetes [7,51,52,53]. In an earlier study on the efficacy and tolerability of long-term administration of carvedilol (1), Nodari et al. [27] evaluated the drug’s effects in patients with chronic heart failure, a number of whom were also diabetic. Treatment with increasing doses of carvedilol was well tolerated by all treated patients, showing positive effects on left ventricular function and on resting and exercise hemodynamics. Furthermore, unlike traditional beta-blockers, it did not affect insulin sensitivity and glycemic values in diabetic patients treated with oral hypoglycemic agents or insulin [27,54,55].
In a separate study, carvedilol (1) was found to be more effective than metoprolol, one of the most prescribed selective beta-1 adrenergic antagonists, in controlling glucose metabolism in diabetic hypertensive patients without affecting insulin resistance [51,54]. This was most likely due to carvedilol’s ability to also block beta-2 and alpha-1 receptors [56]. Unlike patients treated with metoprolol, who gained weight after 2 months of treatment, no significant change in body weight was observed in those treated with carvedilol (1). Long-term carvedilol treatment may have beneficial effects on endothelial dysfunction caused by oxidative stress in patients with type 2 DM. This could be due to the antioxidant properties of the compound, which acts as a radical scavenger, and to its capability to modulate endothelial NO production [28,57].
Vardeny et al., in 2012 [29], found that in hypertensive patients treated with metoprolol succinate, after six months, insulin levels increased by approximately 36%, whereas a decrease of about 10% was observed in those treated with carvedilol (1) (p = 0.015).
Many studies have discovered a relation between β2-AR polymorphisms and metabolic disorders, including hypertriglyceridemia, insulin resistance, and obesity [58,59,60]. In particular, two common β2-AR single-nucleotide polymorphisms, Arg16Gly and Gln27Glu, have been shown to be responsible for altered receptor function and, consequently, for an inadequate response to β-blocker treatment.
Farhat et al., in 2019, demonstrated that low-dose carvedilol (1) can efficiently prevent hypoglycemic crises in rats treated with β-blockers. This study showed that rats with recurrent episodes of hypoglycemia treated with carvedilol required less exogenous glucose during the hypoglycemic clamp, thus supporting use of the drug to preserve hormonal responses to hypoglycemia. Furthermore, carvedilol treatment had no effect on plasma lactate levels, indicating that the drug can prevent some of the central adaptations that occur during recurrent hypoglycemic episodes [61].
In 2017, Nardotto et al. [30] conducted a study aimed at evaluating the pharmacokinetic profile of the enantiomers of carvedilol and the corresponding metabolites, hydroxyphenylcarvedilol (OHC) (2) and O-desmethylcarvedilol (DMC) (3) (Figure 4), in healthy volunteers and in patients with type 2 DM but with good glycemic control.
For this purpose, thirteen healthy subjects were recruited and divided into two groups: the first group underwent treatment with carvedilol as a single agent, while the second one received a treatment of carvedilol (1) in combination with glibenclamide and metformin. In addition, patients with type 2 DM were enrolled and were treated with carvedilol as a single agent. The results of this study demonstrated that the pharmacokinetic profile of the carvedilol enantiomers did not differ between each other, even in the patients treated with glibenclamide and metformin.
In a separate study, the same authors, using an integrated population pharmacokinetic modeling approach, confirmed that carvedilol does not induce insulin resistance or worsen glycemic control in diabetic hypertensive patients [31]. More recently, Nguyen et al. conducted a study to evaluate the effects of carvedilol (1) treatment in subjects with obesity induced by a high-fat diet (HFD). The findings not only confirmed the improvement in glucose tolerance and insulin sensitivity, but also indicated that these effects are related to the suppression of hepatic glucose overproduction and to the enhancement of the muscle insulin signaling pathway. Hence, as a result of the drug’s ability to block adrenergic hyperactivation, long-term treatment with carvedilol (1) may provide significant benefits in obese subjects [32,60,61].
The efficacy of carvedilol (1) is, however, limited due to its poor bioavailability. Therefore, various studies have been conducted in order to formulate the drug in transport systems capable of guaranteeing the desired therapeutic effect without increasing the dose to be administered. Since a high insulin concentration significantly increases DNA fragmentation, Farahani-Zangaraki et al., in 2021 [7], used the Comet test to assess the genoprotective effects of carvediol included into niosomes against supraphysiological insulin levels in human umbilical vein endothelial cells (HUVEC) [62]. As a result, incorporating carvedilol (1) into the nanoparticles increased efficiency by about fivefold. In particular, treatment of HUVEC cells with niosome-carvedilol (1) nanoparticles 24 h before insulin administration resulted in a significant decrease in DNA fragmentation related to the insulin-treated group, confirming the better genoprotective effect of the drug loaded in the niosomes compared to the free drug. Treatment of HUVEC cells with niosome carvedilol (1) nanoparticles 24 h before insulin administration decreases DNA fragmentation compared to the insulin-treated group, confirming the greater genoprotective effect of the drug loaded in the niosomes compared to the free drug [7].
Recently, carvedilol (1) had also been investigated as an alternative therapeutic strategy for the treatment of type 1 DM. In an in vivo experimental model of type 1 DM, Amirshahrokhi and Zohouri [33] demonstrated carvedilol’s protective effect against pancreatic β-cell damage, confirming the drug’s ability to significantly reduce blood glucose levels, weight loss, and insulitis in pancreatic tissue, as well as the onset of diabetes. Significant increases in the antioxidants glutathione (GSH), superoxide dismutase (SOD), and catalase were observed in pancreatic tissue from carvedilol-treated mice. On the other hand, a reduction in malondialdehyde (MDA), nitric oxide (NO), and myeloperoxidase (MPO) levels was also observed. In addition, the treatment promoted an appreciable reduction in the β-cell damage in pancreatic tissue as well as in the expression of inflammatory modulators including the nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iN-OS). Similarly, a reduction of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 IL-12, IL-17, interferon (IFN)-γ, and chemokine had been also observed, while the expression of anti-inflammatory cytokine IL-10 increased [33].
Despite that the experimental evidence points to carvedilol as having a decidedly positive effect in the treatment of diabetes, more research into the drug’s mechanism of action is required.

2.2. 1,2,4-Triazine-Carbazoles

As already mentioned, α-glucosidase represents a valuable target for the treatment of type 2 DM. As a result, numerous efforts are being made by the scientific community to identify new compounds capable of inhibiting this enzyme in order to delay carbohydrate digestion and glucose absorption, thus leading to a reduction in postprandial glycemia values [63]. Accordingly, in 2016, Wang et al. [6] developed a small series of triazines, used as different starting substitute carbazoles, in order to identify novel α-glucosidase inhibitors.
A number of the newly synthesized compounds showed noteworthy activity against the enzyme. In particular, compound 4 (1-((5,6-di(furan-2-yl) -1,2,4-triazin-3-yl)thio)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol)) (Figure 5) was found to be the most promising, with IC50 values of 4.27 ± 0.07 µM, significantly higher than the control drug acarbose (IC50 = 995.55 ± 2.71 µM).
Molecular docking experiments confirmed its capability to interact with the active site of the enzyme, and furthermore, the kinetic analysis revealed that 4 acts as a non-competitive inhibitor. In particular, the carbazole ring of 4 forms arene-cation interactions with residues Arg-439 and Arg-312, respectively, and the furan ring interacts with residues Leu-176, Phe-157, Phe-177 and Pro-240. Overall, the findings of this study could represent a starting point for the future development of efficient α-glucosidase inhibitors.

2.3. Sulfonamide Carbazole and Carbazole-Containing Cyclic Urea

Variants of the cryptochrome (Cry) gene have been demonstrated to be correlated to the onset of type 2 DM and insulin resistance, as it is involved in glucose homeostasis, control of β-cell function liver lipid content, and the circadian system of mammals [22,64,65].
In order to identify compounds capable of modulating the cryptochrome activity, Humphries et al. in 2016 [35] carried out a systematic SAR study that led to a series of sulfonamide and sulfamide carbazole-based derivatives. Among these compounds, cyclic sulfonamide, 2-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)isothiazoline-1,1-dioxide (5) (Figure 5) was identified as the first small molecule, orally bioavailable, active as a cryptochrome modulator in an in vivo model of type 2 diabetes. The efficacy of this compound was evaluated in mice with diet-induced obesity (DIO), using rosiglitazone as a positive control.
The results obtained by an oral glucose tolerance test confirmed a significantly improved glucose clearance [35]. In 2018, the same research team discovered a new class of carbazole-containing amides and ureas as cryptochrome modulators [22]. In particular, compound 1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-one (6) (Figure 6) resulted as the most promising derivative, implying its potential use in the treatment of metabolic disorders including type 2 DM [22,66,67,68,69].

2.4. Carbazole Triazoles

Recently, a series of derivatives of carbazole linked to a variously substituted triazole have been developed and tested as α-glucosidase inhibitors [36]. The synthesis of these compounds was carried out by a click reaction using N-propargyl-9H-carbazole, acetophenone azide, and a suitable heterocycle as starting reagents. Almost all of the synthesized compounds inhibited the target enzyme more efficiently than acarbose, used as a positive control.
Compounds 2-(4-((9H-carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-(3-bromo-4-hydroxyphenyl) ethanone (7) and 9-((1-(pyridin-3-yl-methyl)-1H-1,2,3-triazol-4-yl) methyl)-9H-carbazole (8) (Figure 7), with IC50 values of 1.0 and 0.8 µM, respectively, resulted as the most promising and thus represent suitable lead compounds for the development of innovative non-sugar derivative antidiabetic agents.

2.5. Tetrahydrocarbazole Derivatives

Zhang et al., in 2018 [37], developed a new series of tetrahydrocarbazoles and tested them in an in vitro assay on human hepatoma cell lines (HepG2) to assess their hypoglycemic activity. Several of the compounds tested exhibited significant activity, with carboxyl (9), 6-(benzyloxy)-9-(chlorobenzoyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (Figure 8) being the most promising. This compound was thus selected for further in vivo experiments. The results obtained confirmed that compound 9 has comparable hypoglycemic properties to that of pioglitazone and causes less weight gain compared to the drug in clinical use.
A recent study [42], reported by the same above research group, led to the identification of an azatetrahydrocarbazole derivative, namely ethyl 8-(benzyloxy)-5-(4-chlorobenzoyl)-7-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (10) (Figure 8). This derivative showed hypoglycemic activity, in cell assays, approximately 1.2 times higher than that of metformin, used as a positive control. Studies aimed at elucidating the mechanism of action responsible for the hypoglycemic activity of these compounds have suggested involvement of the AMP-activated protein kinase (AMPK). The AMPK-mediated pathway plays a key role in controlling the energy and metabolic homeostasis of cells, acting as a sensor for the cellular energy status [70,71].
Compound 10 also showed appreciable chemical stability in gastrointestinal fluids and plasma in in vivo studies, which also confirmed a good tolerance of the compound after oral administration [38]. The promising hypoglycemic, pharmacokinetic, and pharmacodynamic properties of compound 10 validate the potential of carbazole as a versatile scaffold for the preparation of derivatives with improved bioactivities that can be useful in a variety of therapeutic applications.

2.6. Carbazole Alkaloids

Murraya koenigii (L.) Spreng is an endemic plant of India belonging to the Rutaceae family, also known as “meethi neem” or “curry patta” [42]. The extracts of this plant have been extensively investigated for their antidiabetic activity. Recent studies have demonstrated that the main phytocompounds of this plant are alkaloids whose structures contain a carbazole nucleus [42,72,73]. In 2010, Biswas et al. [39] investigated the hypoglycemic effects of mahanine (11) (Figure 9), a carbazole-containing alkaloid, isolated from the leaves of the plant. The results of the experiments on mice with diet-induced diabetes showed a significant reduction in hyperglycemia and insulin resistance, most likely due to the ability of this phytocompound to modulate the expression of the IR gene and the activation of the NF-jB pathway [74].
In a separate study, in addition to mahanine (11), Uvarani et al. isolated from the fruit pulp extract another six carbazole-containing alkaloids: bisgerayafoline D (12), bismahanimbinol (13), bispyrayafoline (14), O-methyl mahanine (15), O-methyl mukonal (16) (Figure 9). All these compounds (11–16) were tested for antioxidant, anti-α-glucosidase, DNA binding, protein interactions, and cytotoxic activities. Out of all the phytochemicals tested, mahanine (11) resulted to be the most promising as a radical scavenger and as an α-glucosidase inhibitor (IC50 of 21.4 ± 0.4 μM). Furthermore, this compound showed cytotoxic activity due to its ability to act as a DNA-intercalating agent [40].
The antidiabetic action of mahanine (11) was also confirmed in a study by Nooron et al. [41] in which the effects of the phytocompound on glucose uptake and translocation of glucose transporter 4 (GLUT4) in skeletal muscle and adipocyte cells were evaluated. In particular, the mahanine (11) treatment promoted a dose-dependent increase in glucose uptake in L6 myotubes and adipocyte cells through the stimulation of the Akt signaling pathway. These findings suggested that mahanine (11) acted similarly to insulin, promoting an enhancement of the Akt-mediated signaling pathway and leading to an increased translocation of GLUT4 on the cell membrane and, consequently, to a higher glucose uptake.
Carbazole-containing alkaloids (16 (Figure 9) and 17–20 (Figure 10)) found in M. koenigii leaf extract promoted a substantial increase in glucose uptake, which was correlated to a higher translocation of GLUT4 into L6-GLUT4myc myotubes. The activity of compounds 16–19 was also investigated in rats with streptozotocin-induced diabetes. Compound 18, koenidine, was found to be the most effective in lowering blood glucose and was therefore selected for further in vivo assays in leptin-receptor-deficient db/db mice. As expected, a significant increase in insulin sensitivity and a progressive lowering of blood glucose level were recorded.
Furthermore, Western blot studies confirmed that the stimulation of GLUT4 translocation observed in L6-GLUT4myc myotubes is mediated by activation of the AKT-modulated signaling pathway. In vitro and in vivo pharmacokinetic studies revealed that compound 18 outperformed the other alkaloids due to its higher metabolic stability and systemic availability. The combination of properties of compound 18 makes it an ideal drug candidate for the treatment of diabetes and the treatment of insulin resistance [42].

2.7. Carbazole-Ethoxy-Phenyl Propionic Acid Derivative

The discovery of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) -α and γ, as primary targets for fibrates and the thiazolidinediones (TZDs), respectively, has opened up new possibilities for the development of alternative tools for the treatment of type 2 DM [75,76].
The ability of TZD and fibrates to lower blood sugar and lipids, respectively, demonstrated in experimental models of insulin resistance and hyperlipidemia, has been known for decades. The improvement in insulin sensitivity promoted by TZDs (pioglitazone or rosiglitazone), although modest, is nevertheless significant and has justified the investments in the search for alternative diabetes treatments, using these compounds as starting compounds [77,78]. Thus far, several computational and in vitro studies on the PPAR receptor have been conducted for this purpose.
One of these research works has led to the identification of compound (S)-3-(4-(2-(9H-carbazol-9-yl)-ethoxy)phenyl)-2-ethoxypropanoic acid (21) (Figure 11), which showed dual activity on both PPAR isoforms α and γ [43]. The results of an oral glucose tolerance test (OGTT) showed that treatment with compound 21 promoted an improvement in insulin sensitivity, greater than that seen with both pioglitazone and rosiglitazone. Compound 21 was also able to lower plasma concentrations of triglycerides and cholesterol in rats fed high cholesterol, whereas treatment with other PPARγ agonists did not have the same results [43].

2.8. Chiglitazar

Chiglitazar (Bilessglu®) (22) (Figure 12) is a small molecule with agonist activity against PPARα, δ and γ, recently developed by Chipscreen Bioscience.
In China, this drug was approved in October 2021 for the treatment of diabetes and is currently in phase II clinical trials for the treatment of non-alcoholic steatohepatitis [44]. In a very recent phase III study [45], the efficacy and safety of chiglitazar (22) were investigated in patients with type 2 DM who were unable to control their blood sugar with diet and exercise alone. Treatment with the drug resulted in significantly better blood glucose control than the placebo, with no significant toxic effects. Multiple administrations of different doses of chiglitazar (22) were generally well tolerated by patients of different ages.
An enhancement in insulin sensitivity and triglyceride level reduction were also recorded. Overall, clinical studies confirmed the drug’s properties observed in preclinical experiments, bolstering the value of PPAR pan-agonists as efficient and safe tools for the treatment of diabetes [46].

3. Conclusions

In conclusion, we covered several studies on carbazoles (Table 2), both of synthetic and natural origin, having a role in the pathogenesis and development of diabetes. Some of these compounds, such as carvedilol (1) and mahanine (11), have been extensively investigated by different research groups, demonstrating a critical role in diabetes control due to their ability to modulate various pathways involved in the onset or evolution of the pathology.
Chiglitazar (22), one of the most promising carbazole derivatives, passed the preclinical experimentation and very recently entered clinical trials.
Important considerations also emerge from the structure–activity relationships of the described carbazole compounds. In particular, it seems that N-substitution with triazinic (see compound 4) or triazolic portions (see compounds 7 and 8) favors α-glucosidase inhibitory activity; the presence of cyclic sulfonamidic (see compound 5) or cyclic urea groups (see compound 6) modulates the cryptochrome activity, whereas the presence of ethylphenoxy groups improves insulin sensitivity (see compounds 21 and 22). Moreover, hydrogenation of a ring of the carbazole core favors the hypoglycemic effect via the AMPK pathway (see compounds 9 and 10), and the tetracyclic system of the mahanine derivatives seems to be important in glucose uptake and translocation of glucose transporter GLUT4 in skeletal muscle and adipocyte cells (see compounds 11, 16–20). Finally compounds with a high conjugation effect show predominant antioxidant activity (see compounds 12–15). Overall, the data herein reported could provide an important reference guide for the development of alternative and effective antidiabetic agents.

Author Contributions

Conceptualization, A.C.; methodology, F.G.; software, G.I.; resources, M.S.S. and C.S.; data curation, A.C. and G.I.; writing—original draft preparation, M.A.O.; writing—review and editing, F.G. and H.E.-K.; supervision, F.G., G.I. and A.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kitabchi, A.E.; Umpierrez, G.E.; Miles, J.M.; Fisher, J.N. Hyperglycemic Crises in Adult Patients with Diabetes. Diabetes Care 2009, 32, 1335–1343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Baron, A.D. Postprandial Hyperglycaemia and Alpha-Glucosidase Inhibitors. Diabetes Res Clin Pract. 1998, 40, S51–S55. [Google Scholar] [CrossRef] [PubMed]
  3. Lebovitz, H.E. Effect of the Postprandial State on Nontraditional Risk Factors. Am. J. Cardiol. 2001, 88, 5H–20H. [Google Scholar] [CrossRef]
  4. Deshpande, A.D.; Harris-Hayes, M.; Schootman, M. Epidemiology of Diabetes and Diabetes-Related Complications. Phys. Ther. 2008, 88, 1254–1264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. López-Candales, A. Metabolic Syndrome X: A Comprehensive Review of the Pathophysiology and Recommended Therapy. J. Med. 2001, 32, 283–300. [Google Scholar]
  6. Wang, G.; Wang, J.; He, D.; Li, X.; Li, J.; Peng, Z. Synthesis and Biological Evaluation of Novel 1,2,4-Triazine Derivatives Bearing Carbazole Moiety as Potent α-Glucosidase Inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 2806–2809. [Google Scholar] [CrossRef] [PubMed]
  7. Farahani-Zangaraki, M.; Taheri, A.; Etebari, M. Niosome-Carvedilol Protects DNA Damage of Supraphysiologic Concentrations of Insulin Using Comet Assay: An in Vitro Study. Hum. Exp. Toxicol. 2021, 40, S150–S157. [Google Scholar] [CrossRef]
  8. Singh, K.; Maity, P.; Krug, L.; Meyer, P.; Treiber, N.; Lucas, T.; Basu, A.; Kochanek, S.; Wlaschek, M.; Geiger, H.; et al. Superoxide Anion Radicals Induce IGF-1 Resistance through Concomitant Activation of PTP 1 B and PTEN. EMBO Mol. Med. 2015, 7, 59–77. [Google Scholar] [CrossRef]
  9. Rostoker, R.; Bitton-Worms, K.; Caspi, A.; Shen-Orr, Z.; LeRoith, D. Investigating New Therapeutic Strategies Targeting Hyperinsulinemia’s Mitogenic Effects in a Female Mouse Breast Cancer Model. Endocrinology 2013, 154, 1701–1710. [Google Scholar] [CrossRef] [Green Version]
  10. Kang, H.J.; Yi, Y.W.; Kim, H.J.; Hong, Y.B.; Seong, Y.S.; Bae, I. BRCA1 Negatively Regulates IGF-1 Expression through an Estrogen-Responsive Element-like Site. Cell Death Dis. 2012, 3, e336. [Google Scholar] [CrossRef] [Green Version]
  11. Babiker, A.; Dubayee, M. Anti-Diabetic Medications: How to Make a Choice? Sudan J. Paediatr. 2017, 17, 11–20. [Google Scholar] [CrossRef]
  12. Saturnino, C.; Grande, F.; Aquaro, S.; Caruso, A.; Iacopetta, D.; Bonomo, M.G.; Longo, P.; Schols, D.; Sinicropi, M.S. Chloro-1,4-Dimethyl-9H-Carbazole Derivatives Displaying Anti-HIV Activity. Molecules 2018, 23, 286. [Google Scholar] [CrossRef] [Green Version]
  13. Ceramella, J.; Iacopetta, D.; Barbarossa, A.; Caruso, A.; Grande, F.; Bonomo, M.G.; Mariconda, A.; Longo, P.; Carmela, S.; Sinicropi, M.S. Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment. Mini Rev. Med. Chem. 2020, 20, 444–465. [Google Scholar] [CrossRef]
  14. Grande, F.; de Bartolo, A.; Occhiuzzi, M.A.; Caruso, A.; Rocca, C.; Pasqua, T.; Carocci, A.; Rago, V.; Angelone, T.; Sinicropi, M.S. Carbazole and Simplified Derivatives: Novel Tools toward β-Adrenergic Receptors Targeting. Appl. Sci. 2021, 11, 5486. [Google Scholar] [CrossRef]
  15. Caruso, A.; Voisin-Chiret, A.S.; Lancelot, J.C.; Sinicropi, M.S.; Garofalo, A.; Rault, S. Efficient and Simple Synthesis of 6-Aryl-1,4-Dimethyl-9H-Carbazoles. Molecules 2008, 13, 1312–1320. [Google Scholar] [CrossRef]
  16. Chakraborty, D.P. Chapter 4 Chemistry and Biology of Carbazole Alkaloids. Alkaloids Chem. Pharmacol. 1993, 44, 257–364. [Google Scholar] [CrossRef]
  17. Sinicropi, M.S.; Iacopetta, D.; Rosano, C.; Randino, R.; Caruso, A.; Saturnino, C.; Muià, N.; Ceramella, J.; Puoci, F.; Rodriquez, M.; et al. N-Thioalkylcarbazoles Derivatives as New Anti-Proliferative Agents: Synthesis, Characterisation and Molecular Mechanism Evaluation. J. Enzym. Inhib. Med. Chem. 2018, 33, 434–444. [Google Scholar] [CrossRef] [Green Version]
  18. Bashir, M.; Bano, A.; Ijaz, A.S.; Chaudhary, B.A. Recent Developments and Biological Activities of N-Substituted Carbazole Derivatives: A Review. Molecules 2015, 20, 13496–13517. [Google Scholar] [CrossRef] [Green Version]
  19. Caruso, A.; Chimento, A.; El-Kashef, H.; Lancelot, J.C.; Panno, A.; Pezzi, V.; Saturnino, C.; Sinicropi, M.S.; Sirianni, R.; Rault, S. Antiproliferative Activity of Some 1,4-Dimethylcarbazoles on Cells That Express Estrogen Receptors: Part, I.J. Enzym. Inhib. Med. Chem. 2012, 27, 609–613. [Google Scholar] [CrossRef] [Green Version]
  20. Caruso, A.; Sinicropi, M.S.; Lancelot, J.C.; El-Kashef, H.; Saturnino, C.; Aubert, G.; Ballandonne, C.; Lesnard, A.; Cresteil, T.; Dallemagne, P.; et al. Synthesis and Evaluation of Cytotoxic Activities of New Guanidines Derived from Carbazoles. Bioorg. Med. Chem. Lett. 2014, 24, 467–472. [Google Scholar] [CrossRef]
  21. Panno, A.; Sinicropi, M.S.; Caruso, A.; El-Kashef, H.; Lancelot, J.C.; Aubert, G.; Lesnard, A.; Cresteil, T.; Rault, S. New Trimethoxybenzamides and Trimethoxyphenylureas Derived from Dimethylcarbazole as Cytotoxic Agents. Part, I.J. Heterocycl. Chem. 2014, 51, E294–E302. [Google Scholar] [CrossRef]
  22. Humphries, P.S.; Bersot, R.; Kincaid, J.; Mabery, E.; McCluskie, K.; Park, T.; Renner, T.; Riegler, E.; Steinfeld, T.; Turtle, E.D.; et al. Carbazole-Containing Amides and Ureas: Discovery of Cryptochrome Modulators as Antihyperglycemic Agents. Bioorg. Med. Chem. Lett. 2018, 28, 293–297. [Google Scholar] [CrossRef]
  23. Sinicropi, M.; Lappano, R.; Caruso, A.; Santolla, M.; Pisano, A.; Rosano, C.; Capasso, A.; Panno, A.; Lancelot, J.; Rault, S.; et al. (6-Bromo-1,4-Dimethyl-9H-Carbazol-3-Yl-Methylene)-Hydrazine (Carbhydraz) Acts as a GPER Agonist in Breast Cancer Cells. Curr. Top. Med. Chem. 2015, 15, 1035–1042. [Google Scholar] [CrossRef] [PubMed]
  24. Saturnino, C.; Caruso, A.; Iacopetta, D.; Rosano, C.; Ceramella, J.; Muià, N.; Mariconda, A.; Bonomo, M.G.; Ponassi, M.; Rosace, G.; et al. Inhibition of Human Topoisomerase II by N,N,N-Trimethylethanammonium Iodide Alkylcarbazole Derivatives. ChemMedChem 2018, 13, 2635–2643. [Google Scholar] [CrossRef] [PubMed]
  25. Saturnino, C.; Sinicropi, M.S.; Iacopettab, D.; Ceramella, J.; Caruso, A.; Muià, N.; Longo, P.; Rosace, G.; Galletta, M.; Ielo, I.; et al. N-Thiocarbazole-Based Gold Nanoparticles: Synthesis, Characterization and Anti-Proliferative Activity Evaluation. IOP Conf. Ser. Mater. Sci. Eng. 2018, 459, 012023. [Google Scholar] [CrossRef]
  26. Caruso, A.; Ceramella, J.; Iacopetta, D.; Saturnino, C.; Mauro, M.V.; Bruno, R.; Aquaro, S.; Sinicropi, M.S. Carbazole Derivatives as Antiviral Agents: An Overview. Molecules 2019, 24, 1912. [Google Scholar] [CrossRef] [Green Version]
  27. Nodari, S.; Metra, M.; Dei Cas, A.; Dei Cas, L. Efficacy and Tolerability of the Long-Term Administration of Carvedilol in Patients with Chronic Heart Failure with and without Concomitant Diabetes Mellitus. Eur. J. Heart Fail. 2003, 5, 803–809. [Google Scholar] [CrossRef] [Green Version]
  28. Kveiborg, B.; Hermann, T.S.; Major-Pedersen, A.; Christiansen, B.; Rask-Madsen, C.; Raunsø, J.; Køber, L.; Torp-Pedersen, C.; Dominguez, H. Metoprolol Compared to Carvedilol Deteriorates Insulin-Stimulated Endothelial Function in Patients with Type 2 Diabetes—A Randomized Study. Cardiovasc Diabetol 2010, 9, 21. [Google Scholar] [CrossRef] [Green Version]
  29. Vardeny, O.; Nicholas, G.; Andrei, A.; Buhr, K.A.; Hermanson, M.P.; Moran, J.J.; Detry, M.A.; Stein, J.H. β-AR Polymorphisms and Glycemic and Lipid Parameters in Hypertensive Individuals Receiving Carvedilol or Metoprolol. Am. J. Hypertens. 2012, 25, 920–926. [Google Scholar] [CrossRef] [Green Version]
  30. Nardotto, G.H.B.; Coelho, E.B.; Paiva, C.E.; Lanchote, V.L. Effects of Type 2 Diabetes Mellitus in Patients on Treatment with Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism. J. Clin. Pharm. 2017, 57, 760–769. [Google Scholar] [CrossRef]
  31. Nardotto, G.H.B.; Lanchote, V.L.; Coelho, E.B.; della Pasqua, O. Population Pharmacokinetics of Carvedilol Enantiomers and Their Metabolites in Healthy Subjects and Type-2 Diabetes Patients. Eur. J. Pharm. Sci. 2017, 109, S108–S115. [Google Scholar] [CrossRef] [PubMed]
  32. Nguyen, L.V.; Ta, Q.V.; Dang, T.B.; Nguyen, P.H.; Nguyen, T.; Pham, T.V.H.; Nguyen, T.H.T.; Baker, S.; le Tran, T.; Yang, D.J.; et al. Carvedilol Improves Glucose Tolerance and Insulin Sensitivity in Treatment of Adrenergic Overdrive in High Fat Diet-Induced Obesity in Mice. PLoS ONE 2019, 14, e0224674. [Google Scholar] [CrossRef]
  33. Amirshahrokhi, K.; Zohouri, A. Carvedilol Prevents Pancreatic β-Cell Damage and the Development of Type 1 Diabetes in Mice by the Inhibition of Proinflammatory Cytokines, NF-ΚB, COX-2, INOS and Oxidative Stress. Cytokine 2021, 138, 155394. [Google Scholar] [CrossRef] [PubMed]
  34. Rahim, F.; Ullah, H.; Javid, M.T.; Wadood, A.; Taha, M.; Ashraf, M.; Shaukat, A.; Junaid, M.; Hussain, S.; Rehman, W.; et al. Synthesis, in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase. Bioorg. Chem. 2015, 62, 15–21. [Google Scholar] [CrossRef] [PubMed]
  35. Humphries, P.S.; Bersot, R.; Kincaid, J.; Mabery, E.; McCluskie, K.; Park, T.; Renner, T.; Riegler, E.; Steinfeld, T.; Turtle, E.D.; et al. Carbazole-Containing Sulfonamides and Sulfamides: Discovery of Cryptochrome Modulators as Antidiabetic Agents. Bioorg. Med. Chem. Lett. 2016, 26, 757–760. [Google Scholar] [CrossRef]
  36. Iqbal, S.; Khan, M.A.; Javaid, K.; Sadiq, R.; Fazal-ur-Rehman, S.; Choudhary, M.I.; Basha, F.Z. New Carbazole Linked 1,2,3-Triazoles as Highly Potent Non-Sugar α-Glucosidase Inhibitors. Bioorg. Chem. 2017, 74, 72–81. [Google Scholar] [CrossRef]
  37. Zhang, J.Q.; Li, S.M.; Ma, X.; Zhong, G.; Chen, R.; Li, X.S.; Zhu, G.F.; Zhou, B.; Guo, B.; Wu, H.S.; et al. Discovery of Tetrahydrocarbazoles with Potent Hypoglycemic and Hypolipemic Activities. Eur. J. Med. Chem. 2018, 150, 102–112. [Google Scholar] [CrossRef]
  38. Wang, L.L.; Du, Y.; Li, S.M.; Cheng, F.; Zhang, N.N.; Chen, R.; Cui, X.; Yang, S.G.; Fan, L.L.; Wang, J.T.; et al. Design, Synthesis and Evaluation of Tetrahydrocarbazole Derivatives as Potential Hypoglycemic Agents. Bioorg. Chem. 2021, 115, 105172. [Google Scholar] [CrossRef]
  39. Biswas, A.; Bhattacharya, S.; Dasgupta, S.; Kundu, R.; Roy, S.S.; Pal, B.C.; Bhattacharya, S. Insulin Resistance Due to Lipid-Induced Signaling Defects Could Be Prevented by Mahanine. Mol. Cell Biochem. 2010, 336, 97–107. [Google Scholar] [CrossRef]
  40. Uvarani, C.; Jaivel, N.; Sankaran, M.; Chandraprakash, K.; Ata, A.; Mohan, P.S. Axially Chiral Biscarbazoles and Biological Evaluation of the Constituents from Murraya Koenigii. Fitoterapia 2014, 94, 10–20. [Google Scholar] [CrossRef]
  41. Nooron, N.; Athipornchai, A.; Suksamrarn, A.; Chiabchalard, A. Mahanine Enhances the Glucose-Lowering Mechanisms in Skeletal Muscle and Adipocyte Cells. Biochem. Biophys. Res. Commun. 2017, 494, 101–106. [Google Scholar] [CrossRef]
  42. Patel, O.P.S.; Mishra, A.; Maurya, R.; Saini, D.; Pandey, J.; Taneja, I.; Raju, K.S.R.; Kanojiya, S.; Shukla, S.K.; Srivastava, M.N.; et al. Naturally Occurring Carbazole Alkaloids from Murraya Koenigii as Potential Antidiabetic Agents. J. Nat. Prod. 2016, 79, 1276–1284. [Google Scholar] [CrossRef]
  43. Sauerberg, P.; Pettersson, I.; Jeppesen, L.; Bury, P.S.; Mogensen, J.P.; Wassermann, K.; Brand, C.L.; Sturis, J.; Wöldike, H.F.; Fleckner, J.; et al. Novel Tricyclic-Alpha-Alkyloxyphenylpropionic Acids: Dual PPARalpha/Gamma Agonists with Hypolipidemic and Antidiabetic Activity. J. Med. Chem. 2002, 45, 789–804. [Google Scholar] [CrossRef]
  44. Deeks, E.D. Chiglitazar: First Approval. Drugs 2022, 82, 87–92. [Google Scholar] [CrossRef]
  45. Ji, L.; Song, W.; Fang, H.; Li, W.; Geng, J.; Wang, Y.; Guo, L.; Cai, H.; Yang, T.; Li, H.; et al. Efficacy and Safety of Chiglitazar, a Novel Peroxisome Proliferator-Activated Receptor Pan-Agonist, in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial (CMAP). Sci. Bull. Beijing 2021, 66, 1571–1580. [Google Scholar] [CrossRef]
  46. Li, X.; Yu, J.; Wu, M.; Li, Q.; Liu, J.; Zhang, H.; Zhu, X.; Li, C.; Zhang, J.; Ning, Z.; et al. Pharmacokinetics and Safety of Chiglitazar, a Peroxisome Proliferator-Activated Receptor Pan-Agonist, in Patients. Clin. Pharm. Drug Dev. 2021, 10, 789–796. [Google Scholar] [CrossRef]
  47. Hercek, R.; Skoda, A.; Proksa, B. Process for Preparation of Carvedilol. U.S. Patent 2006/0167077A1, 19 May 2009. [Google Scholar]
  48. Berridge, M.S.; Nelson, A.D.; Zheng, L.; Leisure, G.P.; Miraldi, F. Specific Beta-Adrenergic Receptor Binding of Carazolol Measured with PET. J. Nucl. Med. 1994, 35, 1665–1676. [Google Scholar]
  49. Fonarow, G.C. Role of Carvedilol Controlled-Release in Cardiovascular Disease. Expert. Rev. Cardiovasc. Ther. 2009, 7, 483–498. [Google Scholar] [CrossRef]
  50. Ahmad, A. Carvedilol Can Replace Insulin in the Treatment of Type 2 Diabetes Mellitus. J. Diabetes Metab. 2017, 8, 2. [Google Scholar] [CrossRef]
  51. Bakris, G.L.; Fonseca, V.; Katholi, R.E.; McGill, J.B.; Messerli, F.H.; Phillips, R.A.; Raskin, P.; Wright, J.T.; Oakes, R.; Lukas, M.A.; et al. Metabolic Effects of Carvedilol vs Metoprolol in Patients with Type 2 Diabetes Mellitus and Hypertension: A Randomized Controlled Trial. JAMA 2004, 292, 2227–2236. [Google Scholar] [CrossRef] [Green Version]
  52. Seferović, P.M.; Petrie, M.C.; Filippatos, G.S.; Anker, S.D.; Rosano, G.; Bauersachs, J.; Paulus, W.J.; Komajda, M.; Cosentino, F.; de Boer, R.A.; et al. Type 2 Diabetes Mellitus and Heart Failure: A Position Statement from the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 2018, 20, 853–872. [Google Scholar] [CrossRef] [Green Version]
  53. Dézsi, C.A.; Szentes, V. The Real Role of B-Blockers in Daily Cardiovascular Therapy. Am. J. Cardiovasc. Drugs 2017, 17, 361–373. [Google Scholar] [CrossRef]
  54. Jacob, S.; Rett, K.; Wicklmayr, M.; Agrawal, B.; Augustin, H.J.; Dietze, G.J. Differential Effect of Chronic Treatment with Two Beta-Blocking Agents on Insulin Sensitivity: The Carvedilol-Metoprolol Study. J. Hypertens. 1996, 14, 489–494. [Google Scholar] [CrossRef]
  55. Refsgaard, J.; Thomsen, C.; Andreasen, F.; Gøtzsche, O. Carvedilol Does Not Alter the Insulin Sensitivity in Patients with Congestive Heart Failure. Eur. J. Heart Fail. 2002, 4, 445–453. [Google Scholar] [CrossRef]
  56. Yue, T.L.; Cheng, H.Y.; Lysko, P.G.; McKenna, P.J.; Feuerstein, R.; Gu, J.L.; Lysko, K.A.; Davis, L.L.; Feuerstein, G. Carvedilol, a New Vasodilator and Beta Adrenoceptor Antagonist, Is an Antioxidant and Free Radical Scavenger. J. Pharm. Exp. Ther. 1992, 263, 92–98. [Google Scholar]
  57. Afonso, R.A.; Patarrao, R.S.; Macedo, M.P.; Carmo, M.M. Carvedilol Action Is Dependent on Endogenous Production of Nitric Oxide. Am. J. Hypertens. 2006, 19, 419–425. [Google Scholar] [CrossRef] [Green Version]
  58. Ehrenborg, E.; Skogsberg, J.; Ruotolo, G.; Large, V.; Eriksson, P.; Arner, P.; Hamsten, A. The Q/E27 Polymorphism in the Beta2-Adrenoceptor Gene Is Associated with Increased Body Weight and Dyslipoproteinaemia Involving Triglyceride-Rich Lipoproteins. J. Intern. Med. 2000, 247, 651–656. [Google Scholar] [CrossRef] [Green Version]
  59. González Sánchez, J.L.; Proenza, A.M.; Martínez Larrad, M.T.; Ramis, J.M.; Fernández Pérez, C.; Palou, A.; Serrano Ríos, M. The Glutamine 27 Glutamic Acid Polymorphism of the Beta2-Adrenoceptor Gene Is Associated with Abdominal Obesity and Greater Risk of Impaired Glucose Tolerance in Men but Not in Women: A Population-Based Study in Spain. Clin. Endocrinol. Oxf. 2003, 59, 476–481. [Google Scholar] [CrossRef]
  60. Suresha, R.N.; Ashwini, V.; Pragathi, B.; Kalabharathi, H.L.; Satish, A.M.; Pushpa, V.H.; Jayanthi, M.K.; Snehalatha, P. The Effect of Carvedilol on Blood Glucose Levels in Normal Albino Rats. J. Clin. Diagn. Res. 2013, 7, 1900–1903. [Google Scholar] [CrossRef]
  61. Farhat, R.; Su, G.; Sejling, A.S.; Knight, N.; Fisher, S.J.; Chan, O. Carvedilol Prevents Counterregulatory Failure and Impaired Hypoglycaemia Awareness in Non-Diabetic Recurrently Hypoglycaemic Rats. Diabetologia 2019, 62, 676–686. [Google Scholar] [CrossRef] [Green Version]
  62. Mishra, J.; Löbmann, K.; Grohganz, H.; Rades, T. Influence of Preparation Technique on Co-Amorphization of Carvedilol with Acidic Amino Acids. Int. J. Pharm. 2018, 552, 407–413. [Google Scholar] [CrossRef]
  63. Ross, S.A.; Gulve, E.A.; Wang, M. Chemistry and Biochemistry of Type 2 Diabetes. Chem. Rev. 2004, 104, 1255–1282. [Google Scholar] [CrossRef]
  64. Bass, J. Circadian Topology of Metabolism. Nature 2012, 491, 348–356. [Google Scholar] [CrossRef]
  65. Marcheva, B.; Ramsey, K.M.; Peek, C.B.; Affinati, A.; Maury, E.; Bass, J. Circadian Clocks and Metabolism. Handb. Exp. Pharm. 2013, 217, 127–155. [Google Scholar] [CrossRef] [Green Version]
  66. Renström, F.; Koivula, R.W.; Varga, T.V.; Hallmans, G.; Mulder, H.; Florez, J.C.; Hu, F.B.; Franks, P.W. Season-Dependent Associations of Circadian Rhythm-Regulating Loci (CRY1, CRY2 and MTNR1B) and Glucose Homeostasis: The GLACIER Study. Diabetologia 2015, 58, 997–1005. [Google Scholar] [CrossRef] [Green Version]
  67. Machicao, F.; Peter, A.; Machann, J.; Konigsrainer, I.; Bohm, A.; Lutz, S.Z.; Heni, M.; Fritsche, A.; Schick, F.; Konigsrainer, A.; et al. Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content. PLoS ONE 2016, 11, e0145563. [Google Scholar] [CrossRef]
  68. Kelly, M.A.; Rees, S.D.; Hydriem, Z.L.; Shera, A.S.; Bellary, S.; O’Hare, J.P.; Kumar, S.; Taheri, S.; Basit, A.; Barnett, A.H. Circadian Gene Variants and Susceptibility to Type 2 Diabetes: A Pilot Study. PLoS ONE 2012, 7, e32670. [Google Scholar] [CrossRef] [Green Version]
  69. Dashti, H.S.; Smith, C.E.; Lee, Y.C.; Parnell, L.D.; Lai, C.Q.; Arnett, D.K.; Ordovás, J.M.; Garaulet, M. CRY1 Circadian Gene Variant Interacts with Carbohydrate Intake for Insulin Resistance in Two Independent Populations: Mediterranean and North American. Chronobiol. Int. 2014, 31, 660–667. [Google Scholar] [CrossRef] [Green Version]
  70. Hardie, D.G. AMP-Activated Protein Kinase: Maintaining Energy Homeostasis at the Cellular and Whole-Body Levels. Annu. Rev. Nutr. 2014, 34, 31–55. [Google Scholar] [CrossRef] [Green Version]
  71. Herzig, S.; Shaw, R.J. AMPK: Guardian of Metabolism and Mitochondrial Homeostasis. Nat. Rev. Mol. Cell Biol. 2018, 19, 121–135. [Google Scholar] [CrossRef] [Green Version]
  72. Caruso, A.; Barbarossa, A.; Carocci, A.; Salzano, G.; Sinicropi, M.S.; Saturnino, C. Carbazole Derivatives as STAT Inhibitors: An Overview. Appl. Sci. 2021, 11, 6192. [Google Scholar] [CrossRef]
  73. Caruso, A.; Iacopetta, D.; Puoci, F.; Rita Cappello, A.; Saturnino, C.; Stefania Sinicropi, M. Carbazole Derivatives: A Promising Scenario for Breast Cancer Treatment. Mini-Rev. Med. Chem. 2016, 16, 630–643. [Google Scholar] [CrossRef] [PubMed]
  74. Santomauro, A.T.M.G.; Boden, G.; Silva, M.E.R.; Rocha, D.M.; Santos, R.F.; Ursich, M.J.M.; Strassmann, P.G.; Wajchenberg, B.L. Overnight Lowering of Free Fatty Acids with Acipimox Improves Insulin Resistance and Glucose Tolerance in Obese Diabetic and Nondiabetic Subjects. Diabetes 1999, 48, 1836–1841. [Google Scholar] [CrossRef] [PubMed]
  75. Willson, T.M.; Cobb, J.E.; Cowan, D.J.; Wiethe, R.W.; Correa, I.D.; Prakash, S.R.; Beck, K.D.; Moore, L.B.; Kliewer, S.A.; Lehmann, J.M. The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor Gamma Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39, 665–668. [Google Scholar] [CrossRef] [PubMed]
  76. Brown, P.J.; Winegar, D.A.; Plunket, K.D.; Moore, L.B.; Lewis, M.C.; Wilson, J.G.; Sundseth, S.S.; Koble, C.S.; Wu, Z.; Chapman, J.M.; et al. A Ureido-Thioisobutyric Acid (GW9578) Is a Subtype-Selective PPARalpha Agonist with Potent Lipid-Lowering Activity. J. Med. Chem. 1999, 42, 3785–3788. [Google Scholar] [CrossRef] [PubMed]
  77. Collins, J.L.; Blanchard, S.G.; Boswell, G.E.; Charifson, P.S.; Cobb, J.E.; Henke, B.R.; Hull-Ryde, E.A.; Kazmierski, W.M.; Lake, D.H.; Leesnitzer, L.M.; et al. N-(2-Benzoylphenyl)-L-Tyrosine PPARgamma Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety. J. Med. Chem. 1998, 41, 5037–5054. [Google Scholar] [CrossRef] [PubMed]
  78. Henke, B.R.; Blanchard, S.G.; Brackeen, M.F.; Brown, K.K.; Cobb, J.E.; Collins, J.L.; Harrington, W.W.; Hashim, M.A.; Hull-Ryde, E.A.; Kaldor, I.; et al. N-(2-Benzoylphenyl)-L-Tyrosine PPARgamma Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents. J. Med. Chem. 1998, 41, 5020–5036. [Google Scholar] [CrossRef]
Applsci 13 00349 g001 550
Figure 1. Mechanisms of action of antidiabetic drugs.
Figure 1. Mechanisms of action of antidiabetic drugs.
Applsci 13 00349 g001
Applsci 13 00349 g002 550
Figure 2. Structure of carbazole (I).
Figure 2. Structure of carbazole (I).
Applsci 13 00349 g002
Applsci 13 00349 g003 550
Figure 3. Structure of carvedilol (1).
Figure 3. Structure of carvedilol (1).
Applsci 13 00349 g003
Applsci 13 00349 g004 550
Figure 4. Structures of: hydroxyphenylcarvedilol (OHC) (2) and O-desmethylcarvedilol (DMC) (3).
Figure 4. Structures of: hydroxyphenylcarvedilol (OHC) (2) and O-desmethylcarvedilol (DMC) (3).
Applsci 13 00349 g004
Applsci 13 00349 g005 550
Figure 5. Structure of 1-((5,6-di(furan-2-yl)-1,2,4-triazin-3-yl)thio)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (4).
Figure 5. Structure of 1-((5,6-di(furan-2-yl)-1,2,4-triazin-3-yl)thio)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (4).
Applsci 13 00349 g005
Applsci 13 00349 g006 550
Figure 6. Structures of: 2-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)isothiazoline-1,1-dioxide (5) and 1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-one (6).
Figure 6. Structures of: 2-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)isothiazoline-1,1-dioxide (5) and 1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-one (6).
Applsci 13 00349 g006
Applsci 13 00349 g007 550
Figure 7. Structures of: 2-(4-((9H-carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-(3-bromo-4-hydroxyphenyl) ethanone (7) and 9-((1-(pyridin-3-yl-methyl)-1H-1,2,3-triazol-4-yl) methyl)-9H-carbazole (8).
Figure 7. Structures of: 2-(4-((9H-carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-(3-bromo-4-hydroxyphenyl) ethanone (7) and 9-((1-(pyridin-3-yl-methyl)-1H-1,2,3-triazol-4-yl) methyl)-9H-carbazole (8).
Applsci 13 00349 g007
Applsci 13 00349 g008 550
Figure 8. Structures of: 6-(benzyloxy)-9-(chlorobenzoyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (9) and ethyl 8-(benzyloxy)-5-(4-chlorobenzoyl)-7-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (10).
Figure 8. Structures of: 6-(benzyloxy)-9-(chlorobenzoyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (9) and ethyl 8-(benzyloxy)-5-(4-chlorobenzoyl)-7-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (10).
Applsci 13 00349 g008
Applsci 13 00349 g009 550
Figure 9. Structures of: mahanine (11), bisgerayafoline D (12), bismahanimbinol (13), bispyrayafoline (14), O-methyl mahanine (15) and O-methyl mukonal (16).
Figure 9. Structures of: mahanine (11), bisgerayafoline D (12), bismahanimbinol (13), bispyrayafoline (14), O-methyl mahanine (15) and O-methyl mukonal (16).
Applsci 13 00349 g009
Applsci 13 00349 g010 550
Figure 10. Structures of: O-methylmurrayamine A (17), koenidine (18), mahanimbine (19) and murrayazoline (20).
Figure 10. Structures of: O-methylmurrayamine A (17), koenidine (18), mahanimbine (19) and murrayazoline (20).
Applsci 13 00349 g010
Applsci 13 00349 g011 550
Figure 11. Structure of (S)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)-2-ethoxypropanoic acid (21).
Figure 11. Structure of (S)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)-2-ethoxypropanoic acid (21).
Applsci 13 00349 g011
Applsci 13 00349 g012 550
Figure 12. Structure of Chiglitazar (22).
Figure 12. Structure of Chiglitazar (22).
Applsci 13 00349 g012
Table
Table 1. Classes of antidiabetic medications.
Table 1. Classes of antidiabetic medications.
DRUG CLASSMECHANISM OF ACTIONMORE COMMON SIDE EFFECTS AND DISADVANTAGES
BIGUANIDES:
Metformin		AMP-Kinase activation;
Decrease in hepatic glucose production.		Gastrointestinal side effects (diarrhea, abdominal cramping);
Lactic acidosis risk;
Vit B12 deficiency;
Hypoxia;
Dehydration.
SULPHONYLUREAS:
Glibenclamide
Gliclazide
Glipizide
Glimepiride		Closure of KATP channels on β cell plasma membranes;
Increase in insulin secretion.		Hypoglycemia;
Weight gain.
GLINIDES (MEGLITINIDES):
Repaglinide
Nateglinide		Closure of KATP channels on β cell plasma membranes;
Increase in insulin secretion.		Hypoglycemia;
Weight gain.
α-GLUCOSIDASE INHIBITORS:
Acarbose
Miglitol		Inhibition of intestinal
α-glucosidase;
Intestinal carbohydrate digestion and absorption reduction.		Generally modest HbA1c efficacy;
Gastrointestinal side effects (flatulence, diarrhea).
THIAZOLIDINEDIONES (TZDs):
Pioglitazone
Rosiglitazone
Lobeglitazone		Nuclear
transcription factor PPAR-γ activation;
Increase in insulin sensitivity.		Weight gain;
Edema;
Heart failure;
Bone fractures.
DPP4 INHIBITORS (GLIPTINS):
Sitagliptin
Vildagliptin
Saxagliptin
Alogliptin
Alogliptin
Linagliptin		DPP-4 inhibition;
Increase in postprandial active incretin (GLP-1, GIP) concentrations;
Increase in glucose-dependent insulin secretion;
Decrease in glucose-dependent glucagon secretion.		Generally modest HbA1c efficacy;
Urticaria;
Angioedema.
GLP-1 AGONISTS:
Exenatide
Liraglutide
Lixisenatide
Dulaglutide		GLP-1 receptors activation;
Increase in glucose-dependent insulin secretion;
Decrease in glucose-dependent glucagon secretion.;
Slowing of gastric emptying;
Satiety increase.		Gastrointestinal side
effects (nausea/vomiting);
Pancreatitis;
C-cell hyperplasia.
SGLT2 INHIBITORS:
Dapagliflozin
Empagliflozin
Canagliflozin		Block of sodium/glucose cotransporter 2 (SGLT2) in renal tubules
Reduction of glucose reabsorption in the kidney;
Decrease in serum blood glucose level.		Renal failure;
Increased risk of genital and urinary trac fungal infection;
Increased risk of euglycemic diabetic ketoacidosis.
AMYLIN ANALOGUES
Pramlintide		Amylin receptors activation;
Glucagon secretion reduction;
Slowing of gastric emptying;
Satiety increase.		Generally modest HbA1c efficacy;
Gastrointestinal side effects
Hypoglycemia.
Table
Table 2. Carbazole derivatives in the pathogenesis of diabetes.
Table 2. Carbazole derivatives in the pathogenesis of diabetes.
CompoundNameBiological ActivityReferences
1
(Synthetic compound)		Carvedilol
(1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol)		Reduction of insulin resistance by sensitizing insulin receptors and inhibiting the sympathetic nervous system
Beneficial effects on left ventricular function, resting and exercise hemodynamics and clinical conditions
Stimulation of endothelial NO production
Beneficial effects on endothelial dysfunction caused by oxidative stress
Long-term benefits on glucose metabolism
Blockade of adrenergic hyperactivation
Prevention of pancreatic β-cell damage
Inhibition of inflammatory and oxidative mediators		[7,27,28,29,30,31,32,33]
2Hydroxyphenyl-carvedilol (OHC)
4-[2-[[3-(9H-Carbaz-ol-4-yloxy)-2-hydroxypro-pyl]amino]ethoxy]-3-methoxyphenol		Metabolite of carvedilol[30]
3O-Desmethylcarvedilol (DMC)
2-[2-[[3-(9H-Carbaz-ol-4-yloxy)-2-hydroxypro-pyl]amino]ethoxy]phenol		Metabolite of carvedilol[30]
4
(Synthetic compound)		1-((5,6-Di(furan-2-yl)-1,2,4-triazin-3-yl)thio)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-olα-Glucosidase inhibition (IC50 = 4.27 ± 0.07 µM)[6,34]
5
(Synthetic compound)		2-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)isothiazoline-1,1-dioxideCryptochrome modulator[35]
6
(Synthetic compound)		1-(3-(3,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-oneCryptochrome modulator[22]
7
(Synthetic compound)		2-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-(3-bromo-4-hydroxyphenyl) ethanoneα-Glucosidase inhibition (IC50 = 1.0 ± 0.057 µM)[36]
8
(Synthetic compound)		9-((1-(Pyridin-3-yl-methyl)-1H-1,2,3-triazol-4-yl) methyl)-9H-carbazoleα-Glucosidase inhibition (IC50 = 0.8 ± 0.01 µM)[36]
9
(Synthetic compound)		6-(Benzyloxy)-9-(4-chlorobenzoyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acidHypoglycemic effect via the AMPK pathway[37]
10
(Synthetic compound)		Ethyl 8-(benzyloxy)-5-(4-chlorobenzoyl)-7-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylateHypoglycemic effect via the AMPK pathway[38]
11
(Naturalcompound)		Mahanine
3,5-Dimethyl-3-(4-methylpent-3-enyl)-11H-pyrano[3,2-a]carbazol-9-ol		Prevention of insulin resistance due to lipid induced signaling defects
α-Glucosidase inhibition (IC50 = 21.4 ± 0.4 μM)
Antioxidant properties
Increase in the translocation of GLUT4 protein from intracellular vesicles into the plasma fraction and glucose uptake through the activation of phosphorylation of Akt		[39,40,41]
12
(Naturalcompound)		Bisgerayafoline D
3,3′-Bis((E)-3,7-dimethylocta-2,6-dien-1-yl)-9′-methoxy-3,3′,5,5′-tetramethyl-3,3′,11,11′-tetrahydro-[9,10′-bipyrano[3,2-a]carbazol]-10-ol		Antioxidant and α-glucosidase properties[40]
13
(Naturalcompound)		Bismahanimbinol
3,3′,5,5′-Tetramethyl-3,3′-bis(4-methylpent-3-en-1-yl)-3,3′,11,11′-tetrahydro-[9,10′-bipyrano[3,2-a]carbazol]-8-ol		Antioxidant and α-glucosidase properties[40]
14
(Naturalcompound)		Bispyrayafoline
3,3′,5,5′-Tetramethyl-3,3′-bis(4-methylpent-3-en-1-yl)-3,3′,11,11′-tetrahydro-[10,10′-bipyrano [3,2-a]carbazole]-9,9′-diol		Antioxidant and α-glucosidase properties[40]
15
(Naturalcompound)		O-Methyl mahanine
9-Methoxy-3,5-dimethyl-3-(4-methylpent-3-en-1-yl)-3,11-dihydropyrano[3,2-a]carbazole		Antioxidant and α-glucosidase properties[40]
16
(Naturalcompound)		O-Methyl mukonal
Koenimbine
8-Methoxy-3,3,5-trimethyl-11H-pyrano[3,2-a]carbazole		Antioxidant and α-glucosidase properties
Antidiabetic activity in L6-GLUT4 myc myotubes		[40,42]
17
(Naturalcompound)		O-Methylmurrayamine A
9-Methoxy-3,3,5-trimethyl-11H-pyrano[3,2-a]carbazole		Antidiabetic activity in L6-GLUT4 myc myotubes
Decrease in blood glucose profile		[42]
18
(Naturalcompound)		Koenidine
8,9-Dimethoxy-3,3,5-trimethyl-11H-pyrano [3,2-a]carbazole		Antidiabetic activity in L6-GLUT4myc myotubes
Increase in insulin sensitivity and progressive reduction of blood glucose level		[42]
19
(Naturalcompound)		Mahanimbine
3,5-Dimethyl-3-(4-methylpent-3-enyl)-11H-pyrano[3,2-a]carbazole		Antidiabetic activity in L6-GLUT4myc myotubes[42]
20
(Naturalcompound)		Murrayazoline
(14R,17S,19S)-3,13,13,17-Tetramethyl-21-oxa-12-azahexacyclo[10.7.1.12,17.05,20.06,11.014,19]henicosa-1,3,5(20),6,8,10-hexaene		Antidiabetic activity in L6-GLUT4myc myotubes[42]
21
(Synthetic compound)		(S)-3-(4-(2-(9H-Carbazol-9-yl)ethoxy)phenyl)-2-ethoxypropanoic acidImprove of the insulin sensitivity
Activity on PPARR and PPARγ		[43]
22
(Synthetic compound)		Chiglitazar
(2S)-3-[4-(2-Carbazol-9-ylethoxy)phenyl]-2-[2-(4-fluorobenzoyl)anilino]propanoic acid		Reduction of glycosylated hemoglobin A1c (HbA1c)
Hypoglycemic effect
Increase in insulin sensitivity
Reduction of triglycerides		[44,45,46]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Grande, F.; Ioele, G.; Caruso, A.; Occhiuzzi, M.A.; El-Kashef, H.; Saturnino, C.; Sinicropi, M.S. Carbazoles: Role and Functions in Fighting Diabetes. Appl. Sci. 2023, 13, 349. https://doi.org/10.3390/app13010349

AMA Style

Grande F, Ioele G, Caruso A, Occhiuzzi MA, El-Kashef H, Saturnino C, Sinicropi MS. Carbazoles: Role and Functions in Fighting Diabetes. Applied Sciences. 2023; 13(1):349. https://doi.org/10.3390/app13010349

Chicago/Turabian Style

Grande, Fedora, Giuseppina Ioele, Anna Caruso, Maria Antonietta Occhiuzzi, Hussein El-Kashef, Carmela Saturnino, and Maria Stefania Sinicropi. 2023. "Carbazoles: Role and Functions in Fighting Diabetes" Applied Sciences 13, no. 1: 349. https://doi.org/10.3390/app13010349

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop