European Journal of Medicinal Chemistry 92 (2015) 839e865

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Mini-review

Chalcones and their therapeutic targets for the management of

diabetes: Structural and pharmacological perspectives
Debarshi Kar Mahapatra, Vivek Asati, Sanjay Kumar Bharti*
Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur 495009, Chhattisgarh, India

a r t i c l e i n f o a b s t r a c t

Article history: Diabetes Mellitus (DM) is the fastest growing metabolic disorder affecting about 387 million people
Received 2 December 2014 across the globe and is estimated to affect 592 million people by year 2030. The search for newer anti-
Received in revised form diabetic agents is the foremost need to control the accelerating diabetic population. Several natural and
23 January 2015
(semi) synthetic chalcones deserve the credit of being potential candidates that act by modulating the
Accepted 24 January 2015
Available online 26 January 2015
therapeutic targets PPAR-g, DPP-4, a-glucosidase, PTP1B, aldose reductase, and stimulate insulin secre-
tion and tissue sensitivity. In this review, a comprehensive study (from January 1977 to October 2014) of
anti-diabetic chalcones, their molecular targets, structure activity relationships (SARs), mechanism of
Keywords:
Chalcone
actions (MOAs) and patents have been described. The compounds which showed promising activity and
Diabetes have a well-defined MOAs, SARs must be considered as prototype for the design and development of
DPP-4 potential anti-diabetic agents. They should be evaluated critically at all clinical stages to ensure their
a-Glucosidase therapeutic and toxicological profile to meet the demand of diabetics.
PPAR-g © 2015 Elsevier Masson SAS. All rights reserved.
PTP1B

1. Introduction Insulin is secreted into the blood stream by b-cells of pancreas.

Insulin receptor substrate (IRS) 1 and 2 play dominant role in this
DM is a chronic metabolic disorder of carbohydrate, fat and cascade when secreted insulin binds to the a-subunit on the
protein metabolism characterized by high blood sugar, either extracellular surface of the cell and activates tyrosine kinase ac-
because the body does not produce enough insulin that is required tivity in the intracellular portion of the b-subunit, which simulta-
to convert sugar, starches, and other food into energy (Type I dia- neously promotes autophosphorylation of the insulin b-receptor
betes) or because cells do not properly use insulin (Type II diabetes) subunit and phosphorylation of tyrosine residues on cytoplasmic
[1]. Insulin is a major anabolic hormone in the regulation of blood proteins. Phosphatidyl Inositol 3-Kinase (PI3K) becomes activated
glucose concentrations and energy metabolism [2]. It is essential and dimerizes with its catalytic subunit, thereby promotes trans-
for glycogen formation in liver, glucose conversion into tri- location of glucose transporters to the cell membrane surface,
glycerides, nucleic acid synthesis, protein synthesis and transport which promotes hexose transport and amplify glucose uptake by
of glucose and amino acids across the membrane [3]. Maintenance glucose transporter type 4 (GLUT4) in fatty tissues and skeletal
of glucose homeostasis is achieved by the hormonal regulation of muscle. Glucose enters b-cells through glucose transporter type 2
glucose uptake and endogenous glucose production, primarily by (GLUT 2) and is phosphorylated by glucokinase. This results in
muscle and liver. A change in normal glucose homeostasis occurs by generation of ATP from glycolysis, which causes an increase of
a combination of factors which include impaired insulin secretion, intracellular ATP/ADP ratio. The produced ATPs, consequently bind
unconcealed hepatic gluconeogenesis and reduced uptake of with ATP-dependent Kþ channels at the membrane of b-cells,
glucose by skeletal muscle, adipose tissues and liver resulting in which results in closing of these channels and depolarization of
hyperglycemic condition referred as Diabetes Mellitus (DM) [4]. cells. This depolarization activates voltage-sensitive calcium
The most prominent feature of type II diabetes is decreased channels causing a calcium influx which triggers insulin secretion.
sensitivity of muscle and adipose cells to insulin. The symptoms are Insulin secretion occurs in two distinct phases from pancreatic b-
depicted in Fig. 1. cells affects the magnitude of both postprandial and fasting blood
glucose concentrations. Initially, a rapid release of insulin occurs
when the glucose concentration increases concurrently after a
* Corresponding author. meal, which is followed by a phase of sustained increase in circu-
E-mail address: [Link]@[Link] (S.K. Bharti). lating insulin concentrations [5e8].

[Link]
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.
840 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865

Fig. 1. Symptoms of diabetes mellitus (DM).

DM is the fastest progressing metabolic disorder prevailing successful treatment of diabetes and its related complications.
mostly in low and middle income nations. Currently, 387 million There are mainly five classes of therapeutic agents having different
people worldwide are affected and is predicted to affect 592 million mechanism of actions and used commonly to treat hyperglycemia.
in 2030 [9]. DM caused 4.9 million deaths in year 2014 and is still The a-glucosidase inhibitors, aldose reductase (ALR) inhibitors,
counting. It is also predicted to be the 7th root cause of death in dipeptidyl peptidase-4 (DPP-4) inhibitors, protein tyrosine phos-
2030 [10]. About 29.1 million people in United States are affected by phatase 1B (PTP1B) inhibitors and peroxisome proliferator-
DM with 27.8% people being diagnosed successfully. Genetic sus- activated receptor-g (PPAR-g) activators are commonly used to
ceptibility is still a major suspicion for scientists across the globe; treat diabetes but they produce various complications. Natural and
however the data published by NDSR, 2014 strongly supports the semi (synthetic) chalcones have shown significant anti-diabetic
statement with a sturdy conclusion that among hispanic adults, the property devoid of associated complications.
age-adjusted rate of diagnosed diabetes was 8.5% for Central and
South Americans, 9.3% for Cubans, 13.9% for Mexican Americans, 2. Chalcones
and 14.8% for Puerto Ricans [11]. The fastest growing ethnic group
with diagnosed diabetes is expected to be black males (þ363% from The privileged scaffold chalcone remained a fascination among
2000 to 2050), with black females (þ217%), white males (þ148%), researchers in the 21st Century due to its simple chemistry, ease of
and white females (þ107%) following [12]. Not only people synthesis, diversity of substituents, wide range of biological activ-
involved in regular sedentary work are affected, a recently study ities such as anti-diabetic [16], anti-neoplastic [17], anti-
revealed that rural people are equally vulnerable to DM. A study hypertensive [18], anti-retroviral [19], anti-inflammatory [20],
conducted at rural population of Indian state Karnataka reveals that anti-parasital [21], anti-histaminic [22], anti-malarial [23], anti-
people from different low socio-economic strata showed preva- oxidant [24], anti-fungal [25], anti-obesity [26], anti-platelet [27],
lence of about 89.3% out of 3000 individuals [13]. In 2012, 86 anti-tubercular [28], immunosuppressant [29], anti-arrhythmic
million Americans age 20 and older had pre-diabetes, a condition in [30], hypnotic [31], anti-gout [32], anxiolytic [33], anti-spasmodic
which blood glucose are higher than normal but are not high [34], anti-nociceptive [35], hypolipidemic [36], anti-filarial [37],
enough for a diagnosis the determination of a disease. Diabetes anti-angiogenic [38], anti-protozoal [39], anti-bacterial [40], anti-
remains the 7th leading cause of death in the United States in with a steroidal [41], etc. The term “chalcone” was coined by Kostanecki,
total of 2,34,051 death certificates listing diabetes as an underlying who synthesized a series of natural chromophoric products for the
or contributing cause of death [14]. Europe is not far behind first time. Chalcone (1,3-diphenyl-2E-propene-1-one) is an open
regarding DM progression, UK records for about 3.2 million people chain intermediate in aurones synthesis of flavones that exists in
with high prevalence among populations of northern region; many conjugated forms in nature [42,43]. It contains a benzylide-
specially Wales (6.7%), Scotland (5.6%) and Ireland (5.3%) [15]. neacetophenone scaffold where the two aromatic nuclei are joined
For pharmacotherapy, those compounds that increase the by a three carbon a, b unsaturated carbonyl bridge [44]. Chalcones
sensitivity of muscle and adipose to insulin are foremost choice for are reported to be precursors of flavonoids and isoflavonoids.
 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 841

Chalcones and their derivatives can be synthesized classically by intermediate and release of phosphate [50]. Chalcones play a major
ClaiseneSchmidt condensation between benzaldehyde and aceto- role in the inhibition of PTP1B and used to treat/manage diabetes
phenone employing solution of sodium hydroxide (40%) as catalyst and associated complications. The biochemical processes of glucose
[45]. Newer methods have also been reported where irradiation utilization, involvement of receptor PTP1B and chalcones have been
with domestic microwave is employed to synthesize the com- presented in Fig. 2.
pounds [46]. Licochalcone A was isolated from Glycyrrhiza inflata and its
synthetic derivatives were reported as inhibitor of PTP1B. The
isolated chalcones include isoliquiritigenin (1), echinatin (2), lico-
2.1. Molecular targets of anti-diabetic chalcones chalcone A (3), licochalcone C (4) and licochalcone E (5) and their
synthetic derivatives were formed from compounds (6) and (7) by
2.1.1. Chalcones as PTP1B inhibitors methylation of licochalcone A. Compounds (8) and (9) were also
Protein kinases and phosphatases are groups of enzymes that obtained by direct acetylation of licochalcone A. Compounds (10)
control a number of essential cellular functions via phosphorylation and (11) were prepared by THP-protection of the 4-hydroxy group
and de-phosphorylation reactions. Among Protein Tyrosine Phos- in the A ring followed by methylation or acetylation of the 4-
phatases (PTPs), Protein Tyrosine Phosphatase 1B (PTP1B) has hydroxyl group in the B ring and subsequent cleavage of the THP-
received much attention due to its pivotal role in type II diabetes ether under acidic conditions. Acetylation of compound (6) and
and obesity as a negative regulator of the insulin and leptin- compound (10) with acetic anhydride gave compounds (12) and
signaling pathway. PTP1B is an intercellular non-receptor Protein (13). The licochalcone A derivative (6) showed highest activity [51].
Tyrosine Phosphatase, a prime enzyme responsible for the negative
regulation of the insulin signaling pathway and also acts as a po-
tential drug target for the treatment of type 2 diabetes (t2D) [47,48].
It acts by dephosphorylation of specific phosphotyrosine residues
on the insulin receptor and insulin receptor substrate proteins [49].
PTP-mediated catalysis proceeds via two-step mechanism where in
the initial step, a nucleophilic attack by the sulfur atom of the
thiolate side chain of the Cys on the substrate phosphate, coupled
with protonation of the tyrosyl-leaving group of the substrate by
the side chain of a conserved acidic residue (Asp181 in PTP1B)
acting as a general acid. This leads to formation of a cysteinyl-
phosphate catalytic intermediate. In the later step, mediated by
Gln 262, which coordinates a water molecule, and Asp181, which
functions as a general base, there is hydrolysis of the catalytic

Fig. 2. Chalcone derivatives as PTP1B inhibitors.

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Chen et al. reported twenty novel heterocyclic ring- where eight derivatives (15e22) showed better inhibitory activity
substituted chalcone derivatives as potent inhibitor of PTP1B than the parent moiety (14) [52].
 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 843

Six trihydroxy chalcone derivatives (23e28) have been reported potency of (29) upto 3 times with respect to (30). Therefore, the
as promising candidates for PTP1B inhibition. Authors compared all order of inhibitory activity of chalcone-derived DielseAlder-type
synthesized compounds with compound (28) and concluded that compounds were 29 > 30 > 31. Authors also concluded that the
the electron-donating groups on the B ring showed better inhibi- hydroxyl groups not only provided the needed penetration into
tory activity [53]. the active site but also likely to produce an effective hydrogen

Three methylcyclohexene substituted chalcones derived bonding interaction with the amide backbone of the active-site
DielseAlder type compounds were isolated from Morus bomby- loop. Thus, these facts suggest that with an increase in number
cis; namely, kuwanon J (29), kuwanon R (30) and kuwanon V of OH groups in chalcone-derived DielseAlder-type compounds,
(31). All these chalcone derivatives showed remarkable inhibi- the potential inhibitory effects against PTP1B increases tremen-
tion of PTP1B with IC50 in range of 2.7e13.8 mM in mixedetype dously [54].

manner. Authors concluded that compound (31), possesses OH A series of furan chalcone derivatives were reported as PTP1B
groups at C-40 , C-2, C-4, C-1100, C-1300 and C-1800 exhibited strong inhibitor where two compounds (32) and (33) showed most
dose-independent inhibition, but found to be less potent than effective inhibition in competitive manner as experimentally dis-
(30), which contains one more OH group at C-1600 . Compound played by IC50 values of 2.49 and 2.9 respectively. The hydroxylated
(29) shows structural similarity with (30), except an additional derivatives containing 2-OH (34), 3-OH (35) and 2, 4-OH (32)
OH group at C-2. This additional functionality increases the showed better activity [55].
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Fig. 3. SARs of PTP1B inhibitors.

Chen et al. isolated Broussochalcone (36) from Broussonetia

papyrifa and reported to effectively inhibit PTP1B with IC50 of
21.5 mM. It may be assumed that with increase in hydroxyl groups,
the inhibitory activity increases simultaneously. Broussochalcone
having two hydroxyl groups at both the rings are essential for
effective inhibition [56].

2.1.2. SAR

 Allyl group at position 5 in the B ring is important for exhibiting

significant inhibitory effects.
 Methylation at 4-hydroxy position of ring B increased (two-fold)
activity.
 Substituent (R) with electron-donating groups on the B ring
Na et al. isolated novel chalcone, abyssinone-VI-4-O-methyl showed better or comparative activity, whereas substitution by
ether from ethyl acetate-soluble extract of the root bark of Erythrina the withdrawing groups resulted in a decrease or loss of po-
mildbraedii and evaluated for in vitro PTP1B inhibitory activity. tency, which reflects that electron-donating groups contributed
Authors reported that chalcone (37) showed inhibition of PTP1B more to the inhibitory activity of PTP1B than the electron-
with IC50 value of 14.8 mM [57]. withdrawing groups (Fig. 3).
 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 845

Fig. 4. Mechanism of a-glucosidase inhibition by chalcones.

 The electron-donating groups increased the electron density of Seo et al. reported eight new sulfonamide chalcones (38e45) as
the B ring which results in a more affinitive piepi interaction effective inhibitor of a-glucosidase. The compounds (42e45)
with Tyr46. showed promising activity in inhibiting a-glucosidase [59]. The
 Methylation at C-3; dimethylation at C-3 and C-4; methylation inhibitory activity studied by molecular docking of non-sugar/sugar
at C-3 and O-allyloxylation at C-4 of ring B produced more derivatives suggested that NH group plays an important role in
pronounced PTP1B inhibitory activity. binding to the active site and terminal glycosidic ring interacts with
 Introduction of two hydroxyl groups at the 2- and 4-position of Tyr-171 and Phe-177 of hydrophobic region. The molecular dy-
the A ring dramatically improved PTP1B inhibitory activity. namics simulation studies revealed the exact binding mechanism
 Increasing the number of hydroxyl groups on the A ring in of chalcone derivatives with protein [61]. Other novel chalcones
chalcones leads to stronger binding and improves PTP1B (46e49) were isolated from roots of Broussonetia papyrifera and
inhibitory activity. reported to exhibit a-glucosidase inhibition in non-competitive
 Electron-withdrawing groups on ring A showed better PTP1B manner with IC50 values in range 5.3e19.1 mm [62]. Xanthohumol
inhibitory activity than the compounds containing electron- (XN) (50) showed inhibition of a-glucosidase in a reversible and
donating groups. noncompetitive manner with an IC50 value of 8.8 mM and inhibited
the release of glucose from the maltose in the apical side of the
caco-2 cell monolayer [63]. A series of novel oleanolic acid deriv-
2.2. Chalcones as a-glucosidase inhibitors ativeechalcone conjugates (51e53) as a-glucosidase inhibitors

a-Glucosidases are exo-acting carbohydrases, located at brush

border epithelium of small intestine mucosa, which catalyzes
the release of a-D-glucopyranose from non-reducing ends of
substrates by cleaving terminal non-reducing 1,4 linked a-
glucose and plays important role in the processing of glycopro-
teins and glycolipids [58]. Chalcones play an important role in
inhibition of a-glucosidase (Fig. 4) which leads to decreased
uptake of dietary carbohydrates that suppress postprandial hy-
perglycemia without increasing insulin level, which is useful to
treat diabetic and/or obese patients [59]. Continuous blockade of
enzyme by these “starch blockers” results in simultaneous
reduction in body weight, HbA1c level and serum triglyceride
[60]. Fig. 5. SARs of a-glucosidase inhibitors.
846 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865

were synthesized. Among them, the conjugate (51) possessed the the chalcone units of the conjugates enhanced activity and these
strongest a-glucosidase inhibitory activity; of which the structur- conjugates exhibited significant inhibitory activity toward a-
eeactivity relationships showed that furan or thiophene rings in glucosidase via a competitive mechanism [64].
848 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865

Fig. 6. Chalcones as Aldose Reductase (ALR) inhibitors.

2.2.1. SAR aggravates many diabetic complications such as cataract, retinop-

athy, neuropathy and nephropathy etc. Neuropathic pain is a
 Sulfonamide groups at 3 and/or 4-position of ring A result in detrimental condition characterized by sensation of paresthesia,
increased a-glucosidase inhibition. numbness and burning, caused by the sustained and abnormal
 Increased number of OH groups at 3 and 4-position led to processing of CNS neuronal input. Glucose or its related members
enhanced inhibition (Fig. 5). mediate renal injury, which is also one of the major diabetic com-
plications that have shown fatal results since last decade with
2.3. Chalcones as aldose reductase (ALR) inhibitors millions of deaths. These conditions also affect the quality of life
(QoL) by precipitating other health issues like fatigue, depression
Aldose Reductase (ALR) is an enzyme of polyol pathway that and anxiety [67]. The role of AR is still not clearly understood in
belongs to the aldoeketo reductase (AKR) superfamily. In presence human and is supposed to be an essential enzyme for energy
of cofactor nicotinamide adenine dinucleotide phosphate (NADPH), production of sperm cells only. It is regarded as a necessary evil due
it converts glucose to sorbitol, which is further converted to fruc- to precipitation of secondary diabetic complications, which com-
tose in presence of sorbitol dehydrogenase [65]. The polyol pels a patient to suffer more than its actual pathogenesis. Natural
pathway activates when normal glycolytic cycle gets saturated. As products have been recognized as potential inhibitors of AR and
the alternative route for metabolism, high concentration of glucose among them, chalcone remained the prime choice among re-
in nerve, lens and retina gets metabolized into sorbitol in absence searchers for enzyme inhibition. The biochemical processes of ALR
of insulin, leading to accumulation in tissues, which precipitates have been presented in Fig. 6.
symptoms like osmotic swelling, changes in membrane perme- A series of tri-substituted, heterocyclics and thioglycolic
ability and oxidative stress causing tissue injury [66]. This condition substituted chalcones were synthesized and investigated for ALR1

Fig. 7. SARs of ALR inhibitors.

D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 849

Fig. 8. Mechanism of DPP-4 inhibition by “Chana” based inhibitors.

Fig. 9. Chalcones as PPAR-g activators.

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Fig. 10. SAR of PPAR-g activators.

and ALR2 inhibitory activity by Severi et al. where authors reported

that compounds (54e56) showed effective ALR2 inhibition within a
range of 35e40% [68]. Three chalcones (57e59) were isolated from
Sophora flavescens and have been evaluated against inhibition of
aldose reductase (AR) and generation of advanced glycation end-
products (AGE) at 10 mg/ml. The chalcones showed potent inhibi-
tion of AR in the range of 53.66e74.39% as compared to standard
drug epalrestat (55.56%) [69]. A prosperous component of tradi-
tional Japanese medicine namely isoliquiretigenin (1) was isolated
from Glycyrrhizae radix and reported to have ALR inhibitory activity
in rat lens. It also showed inhibition of hydroxyl accumulation in
human red blood cells (RBCs), sciatic nerve and lens [70].

2.3.1. SAR

 Two hydroxyl groups at 2 and 4-position of the A ring are

essential for optimum activity.
 Saturation of a, b double bond decreased the ALR2 inhibitory
activity in methoxylated compound (Fig. 7).
 Replacement of the aromatic rings with other heterocycles
(pyrrole or pyridine) leads to lower activity.
 The introduction of thioglycolic group in the chalcone ring re-
sults in an increase in activity.

2.4. Chalcones as dipeptidyl peptidase-4 (DPP-4) inhibitors

Dipeptidyl Peptidase- 4 (DPP-4) inhibitors are a novel class of

medication that potentiates the effect of incretin hormones namely
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Fig. 11. Anti-obesity chalcones.

glucagon-like peptide-1 (GLP-1) and glucose-dependent insulino- levels of GLP-1 are low in the fasting state which rises quickly to
topic polypeptide or gastric inhibitory peptide (GIP). These hor- threshold following a meal [72]. When food is taken, a neural
mones are released from the enteroendocrine cells of stimulus and close contact of nutrients with K-and L-cells of mu-
gastrointestinal tract (GIT) into the bloodstream in response to food cosa activates and release GLP-1 from the gastrointestinal tract
intake [71]. GIP is produced by neuroendocrine K-cells and is which causes glucose dependent insulin secretion from the
released in response to fats and to a smaller amount, glucose. It pancreatic b-cells by interacting with insulin receptors in pancreas,
stimulates glucose-dependent release of insulin by binding to the reduces glucagon secretion from the pancreatic a cells, stimulate
highly specific GIP receptors on pancreatic b [Link]-1is the growth, increase survival, proliferation and differentiation of new
most potent incretin hormone and is mainly responsible for b-cells, and slows gastric emptying along with increase in gastric
modulatory effect on the pancreatic b-cell functions. Circulating acid production [73]. Approximately 60% of the postprandial insulin

Fig. 12. Chalcones as SREBP1 inhibitors.

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Fig. 13. mTOR-GSK3b-AS160 pathways: role in insulin resistance.

Fig. 14. SARs of 3-alkylamino-2-hydroxypropoxy chalcones.

release is promoted by these two hormones only. In patient with glucosidase and DPP-4 using in C3H10T1/2 cells. They reported that
type e II diabetes (t2D), continuous subcutaneous infusion of GLP-1 chana 1 (60) and chana 7 showed significant inhibition of a-
leads to reduction in HbA1c levels [74]. GLP-1 has a very short half- glucosidase. In DPP-4 enzyme assay, chana 1 exhibited the highest
life and is rapidly degraded by the enzyme, DPP-4, situated at gut inhibitory activity [16].
mucosa just adjacent to L-cells. About 50% of GLP-1 is degraded
even before it is released from gut mucosa. Renal clearance syn-
ergizes the removal of hormone. DPP-4 cleaves incretins at N-ter-
minal amino acids proline and alanine in the second position, of
which these two amino acids are significant for the biological ac-
tivity of the incretins; GIP and GLP-1, thus, inactivates by its pro-
teolytic activity nature [75]. In order to exploit the beneficial effects
of GLP-1, researchers are focused on strategies to prolong the effect
of GLP-1 and explored the pathway for the treatment/management
of DM. Recently the chalcone inhibitors of “Chana” series have been
developed and showed improved hyperglycemic control in t2D
subjects. The biochemical pathway of DPP-4 has been depicted in
Fig. 8.
Bak et al. synthesized novel “Chana” series of chalcone de-
rivatives and screened for its inhibitory activity against a-
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Fig. 15. SARs of 3,4-methylenedioxy chalcones.

Fig. 16. SARs of naphthyl based chalcones.

2.4.1. SAR

 Replacement of carbonyl group to oxime function showed

enhanced inhibition of DPP-4.

2.5. Chalcones as peroxisome proliferator-activated receptor-g

(PPAR-g) activators

The nuclear peroxisome proliferator-activated receptors (PPARs)

are vital group of proteins that play a major role as essential tran-
scription factors which regulate the expression of genes [76]. PPARs
play crucial role in the regulation of cellular differentiation,
development and metabolism of carbohydrates, lipids and proteins
Fig. 17. SARs of nitro substituted chalcones. in human, of which PPAR-g has pivotal role in glucose homeostasis
[77]. It is expressed at high levels in adipose tissue and requires
heterodimerization with the retinoid X receptor (RXR) for optimal
DNA binding and transcriptional activity [78]. On binding, the
complex of PPAR and RXR binds to specific recognition sites on
DNA, the peroxisome proliferator response elements (PPREs) and
regulates transcription of insulin responsive genes [79]. PPAR-g is
activated by dietary fatty acids and performs different physiological
functions including stimulation of GLUT4 expression and trans-
location leading to in reduction of blood glucose level, suppression
of gluconeogenesis in hepatic tissues, increase in lipid storage and
entry of glucose in muscles [5,80]. Activation of genes of adipose
expanse results in increased insulin sensitizing action. Thiazolidi-
nediones are the most popular ligands but the search for newer and
better agonists is a never ending process. Chalcone conjugated
system revealed its importance as selective agonist on peroxisome
proliferator-activated receptor-g (PPAR-g) (Fig. 9).
Jung et al. have synthesized and evaluated a series of chalcones
and thiazolidinedione derived chalcones (61e63) which showed
Fig. 18. SARs of halogen substituted chalcones. PPAR-g agonist activity [81].
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2.5.1. SAR increase in serum triglyceride level, a sharp elevation in obesity

has been observed and vice-versa [85].
 Methoxy group at position4 of ring B and hydroxyl group at Xanthohumol (60), a multi-targeted chalcone affects triglyc-
position 4 or 5 of ring A in chalcone played a key role in PPAR-g eride synthesis via various inhibitory mechanisms. Casaschi et al.
activation (Fig. 10). first reported the role of xanthohumol on apoB and TAG synthesis
and secretion using HepG2 cells. They concluded that xanthohu-
2.6. Diabeteseobesity relationship and chalcones as anti-obesity mol decreased apoB secretion in a dose-dependent manner under
drugs both basal and lipid-rich conditions by increasing cellular apoB
degradation and inhibiting the synthesis of TG in the microsomal
2.6.1. Chalcones as inhibitor of lipogenesis membrane. The transfer of newly synthesized TAG to the micro-
Patients having DM are associated with various secondary somal lumen indicates TAG availability is a determining factor in
complications which amplifies the deterioration of general con- the regulation of apoB secretion. They also concluded that the
dition. They are 2e4 times more likely to have a risk of coronary inhibition of TAG synthesis was caused by a reduction in diac-
heart disease and stroke. The chronic hyperglycemia of this dis- ylglycerol acyltransferase (DGAT) activity, which corresponded to
ease is associated with long-term dysfunction, damage, and a decrease in DGAT-1 mRNA expression. The microsomal triglyc-
failure of various organs, especially the eyes, kidneys, nerves, eride transfer protein (MTP) may also play a major role in con-
heart, and blood vessels [82]. Triglycerides (TG) are the most trolling the rate of TAG transfer from the microsomal membrane
common form of fat that accounts for 95% of all dietary fats. TGs to the active luminal pool. Xanthohumol decreased MTP activity
are absorbed in the intestines and transported in the blood- in a dose-dependent manner, thus acts as anti-obesity agent
stream to tissues where they are stored as fat only in presence of (Fig. 11) [86]. 4-Hydroxyderricin (64), xanthoangelol (65), carda-
insulin. Because untreated diabetes often includes low insulin monin (66) and flavokawain B (67) are reported to possess anti-
levels, triglycerides aren't moved into your fat cells for later obesity and anti-diabetic actions by targeted inhibition of
conversion to energy. High blood triglycerides are often indicated expression of sterol regulatory element-binding protein-1
due to increased lipolysis of adipose tissues, which increases the (SREBP-1) which is the key molecule involved in lipogenesis. It
risk of developing coronary heart disease [83]. Although high mediates its action by increasing phosphorylation of AMP-
triglyceride levels do not cause diabetes, uncontrolled diabetes activated protein kinase (AMPK) and liver kinase B1 (LKB1).
can elevate triglyceride levels, which further metabolized into These chalcones have also been reported to increase the expres-
very low density lipoprotein (VLDL) with acute reduction of high sion of peroxisome proliferator-activated receptor-a (PPAR-a),
density lipoprotein (HDL) which increases the risk factors of thereby improve fatty acid oxidation (Fig. 12) [87]. Xanthohumol
premature death from heart disease. The combination of high exhibited potential modulating role on farnesoid X receptor (FXR).
triglycerides, high VLDL, low HDL, visceral adiposity and central XN-fed KK-Ay mice exhibited lower levels of plasma glucose and
obesity are the hallmarks of the metabolic syndrome, which hepatic triglyceride. The animal reflected successful features
occurs in 80% of people with type 2 diabetes [84]. This risk is which are essential for diabetotherapy such as significant reduc-
further increased by the presence of other cardiovascular risk tion in white adipose tissue and marked increase in levels of
factors such as smoking, elevated blood cholesterol level, high plasma adiponectin, and proved that XN attenuated diabetes in
blood pressure, obesity, etc. A clear relationship has been re- KK-Ay mice. Additionally, lowered levels of SREBP-1c and gluco-
ported between serum triglyceride level and obesity. With an neogenetic genes were observed [88].
 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 855

of mTOR activates various kinases like serum and glucocorticoid

kinase (SGK) and protein kinase-C (PKC) which mediates cell
proliferation, differentiation and anabolism [92]. This may be due
to increased expression of b-cell. Akt phosphorylation of the Rab
GTPase-activating protein (AS160) leads to dissociation of
insulin-responsive isoform of GLUT4 situated in intracellular
vesicles, which facilitates glucose uptake in adipocytes and
muscle cells by allowing translocation of GLUT4 to the plasma
membrane [93]. Activation of glycogen synthase kinase 3beta
(GSK-3b) by insulin leads to increased stimulation of glycogen
synthase activity which promotes conversion of glucose into
glucagon [94].
AMP-activated protein kinase (AMPK) is a serine/threonine
based protein kinase that acts as an integrating cum monitoring
system for regulation of signals and cellular energy status. AMPK
regulates the coordination of synthesis and storage of glucose
and fatty acids, oxidation of glucose and fatty acids and various
other metabolic processes [95]. Muscle contraction leads to an
increase in AMP/ATP levels which influences an abrupt increase
in AMPK activity which can be correlated with ‘contraction
mediated glucose uptake in muscle’. Activation of AMPK by
2.7. Chalconesas insulin sensitizers for insulin resistant diabetes AICAR (an AMP analogue and known AMPK activator) in muscle
cells constitutively actives AMPK level which increases glucose
In obese, the synthesis of non-esterified fatty acids (NEFAs), uptake simultaneously and causes translocation of the glucose
hormones, interleukins (ILs), adipocyte-derived factors 14 and 19, transporters GLUT1 and GLUT4 to plasma membrane [96]. Thus,
pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), C- AMPK is a potential therapeutic target of metabolic diseases
reactive proteins (CRPs), monocyte chemoattractant protein-1 including t2D and obesity. The activation of AMPK can lead to
(MCP-1) and miscellaneous products of macrophages play crit- increase of glucose uptake into muscle, decreased gluconeogen-
ical role in the development of insulin resistance. Hormones like esis in liver, increased fatty acid oxidation in muscle and liver,
leptin and adiponectin act as an insulin sensitizer which stimu- decreased fatty acid synthesis in liver and adipose tissue and
late fatty acid oxidation in AMP-activated protein kinase (AMPK) increase mitochondrial biogenesis [97]. The mTOR-GSK3b-AS160
through stimulation of both c-Jun amino terminal kinase (JNK) pathways along with AMPK functions are illustrated in Fig. 13.
and the IkB kinase-b (IKK-b)/nuclear factor-kB (NF-kB) pathways, Interruption or blockade of these pathways by above factors, may
thereby upregulating potential mediators of inflammation which lead to development of insulin resistance. A large number of
leads to development of insulin resistance [89,90]. Additionally, chalcone derivatives have been synthesized and screened for
retinol-binding protein-4 (RBP4) plays a role in inducing insulin their hypoglycemic, insulin stimulating/sensitizing and GLUT
resistance by preventing the expression of phosphatidylinositol- expression cum translocation effects by modulating this
3-OH kinase (PI3K) signaling in muscle which is crucial for pathway.
glucose uptake and enhancing expression of phosphoenol pyru- Synthetic chalcone based aryloxypropanolamines have been
vate carboxykinase (PEPCK) in the liver which promotes gluco- reported to possess hyperglycemic property in animal model.
neogenesis [91]. Mammalian target of rapamycin (mTOR) plays a Shukla et al. have reported that these compounds exhibit mod-
major role in obesity induced insulin resistance. Phosphorylation erate to good activity ranging from 6.5% to 31.1% in SLM and
856 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865

8.3%e22.6% in STZ models. The most potent compound (68) significant, acute and lasting antihyperglycemic activity. Com-
exhibited glucose lowering of 26.7% in SLM and 22.6% in STZ pound with nitro group at position 3 or 4 in the B ring showed
models [98]. Similarly, significant hypoglycemic property was different pharmacokinetic/pharmacodynamics profile when
demonstrated by compounds (69e74) in both sucrose loaded administered to the hyperglycemic rats. The compounds with
(SLM) and streptozotocin (STZ) induced diabetic animal models nitro group at position 3 in the B ring (84) showed effective
(Fig. 14) [99]. Prenylated chalcones 4-hydroxyderricin (64) and antihyperglycemic action on serum glucose levels (Fig. 16) [104].
xanthoangelol (65) gained premier importance as anti-diabetic In another study, a series of nitrochalcones demonstrated their
agents. Kawabata et al. have demonstrated their significance ability to increase insulin secretion, in which compounds (85)
which increased 2DG uptake by 1.9 fold at 10 mM in L6 cells as and (86) stimulated insulin secretion by about 325% and
compared to that of DMSO-treated control cells that increased 265%, respectively when compared with the hyperglycemic
muscle contraction, consequently increased glucose uptake control group in the respective time-course of study. Both the
accompanied by the translocation of glucose transporter (GLUT) compounds increased the insulinogenic index 3 folds as
4 [100]. Enoki et al. isolated 4-hydroxyderricin and xan- compared to that of the hyperglycemic control group (Fig. 17) [4].
thoangelol from ethanolic extract from a Japanese herb Angelica A series of chalcones bearing electron donating and electron
keiskei which showed insulin-mimetic activity by a pathway in- withdrawing substitutions and their glucose uptake activity have
dependent of the peroxisome proliferator-activated receptor-g been evaluated and compounds (87e90) showed the most
(PPAR-g) activation [101]. A series of chalcone derivatives effective glucose uptake property (Fig. 18) [105]. Patent
(75e79) have been investigated as antihyperglycemic agents in CN103254053A described an invention related to alpha-
glucose loaded animal model by comparing the biological ac- fluorochalcone type compound that mediates its anti-diabetic
tivity with lispro, regular insulin and tolbutamide. Compounds action by activating/increasing the expression of AMP-mediated
(75) and (77) exhibited the most potent effect; 96% similar to protein kinase. Three compounds (91e93) which showed effec-
that demonstrated by lispro insulin and tolbutamide at 60 min, tive activation of AMPK have been presented in the review [106].
with rapid and lasting effect observed with compound (78) and Patent CN103734842A (Table 1) describes a beverage
(79) (Fig. 15) [102]. Few chalcone derivatives have the potential prepared from A. keiskei and capable of decreasing blood sugar
as insulin sensitizer, where authors reported that compound (80) level. The active constituents are supposed to mediate the
stimulated glucose uptake and potentiated insulin-stimulated pharmacological event as described by Kawabata et al. [107].
glucose uptake in a concentration-dependent manner in 3T3-L1 Patent US7807712B2 describes the synthesis of alkoxy
adipocytes. When cells were treated with insulin in the presence substituted chalcone derivatives which exhibit pronounced
of compound (80), noticeable improvement of insulin-stimulated anti-hyperglycemic and anti-lipedemic activity. Compounds
glucose uptake was observed. Compound (81) showed the most (94e95) showed the most promising anti-diabetic activity [108].
potent sensitization. Substitution by acidic or highly polar groups Orally administrated synthetic sulfonylurea-chalcones hybrid
abolishes the activity completely [103]. Rawat et al. synthesized (96e98) were screened on blood glucose levels and reported to
some chalcones from unprotected sugar and phloroacetophenone reduce the normal blood glucose levels in normoglycemic
and evaluated for their in vitro and in vivo antihyperglycemic rabbits. Compound (98) with dichlorophenyl moiety was found
activity employing glucose uptake by rat muscle cell lines (L-6) to be the most potent hypoglycemic agent with percentage
and low dosage streptozotocin-induced diabetic rats. Authors blood glucose reduction (38.73) at 4 h [109]. Gaur et al. reported
reported that compound (82) lowered the blood glucose levels that ISL derivatives (99e102) showed significant blood
by 34.9% and 33.6% during 0e5 h and 0e24 h, respectively at the glucose lowering effect. The structureeactivity relationship
dose of 25 mg/kg body weight which is comparable to that of indicated that the presence of ether and ester groups in ISL and
standard antidiabetic drug metformin [1]. A series of naphthyl LTG analogues are important for exhibiting the activity. Com-
chalcones have been evaluated as antihyperglycemic agents in pound (99) was selected for best in vivo anti-diabetic activity
glucose loaded animal model for their insulin secretion and and found to be potential candidates for treatment of diabetes
glucose uptake properties. The results showed that the most [110].
effective derivatives (83) and (84) were able to decrease serum
glucose levels in hyperglycemic rats. Nitro group at position 3
and 4 in the A ring and 2-naphthyl group in B ring (83) showed
D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 857
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D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 859
860 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865
 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 861

2.7.1. SAR boon for diabetes in this decade by providing more effective
sugar control in hyperglycemic patients without compromising
 Substitution of 3-alkylamino-2-hydroxypropoxy group at two normal quality of life. Sugars dispensed in various food stuffs
different positions either at 3- or 4- did not exhibit much like sweets, candies, beverages, etc. tend to increase glucose
striking difference in activity profile (Fig. 14). levels in diabetic patients along with intake of unwanted calories,
 Substitution at para position of ring B exhibited better activity which promotes weight gain; particularly visceral adiposity
than meta substituted in SLM model. [112]. The root cause of tooth decay and increased incidence of
 Compound without substituent in the A-ring did not exhibit any dental caries are mediated by long term intake of sugars by
significant changes in glycemic levels. patient suffering from DM [113,114]. A number of chalcone de-
 Substitutions at position 3 and/or 4 in the A-ring caused sig- rivatives have been reported to be excellent sugar substitute
nificant reduction in serum glucose levels (Fig. 15). with sweetening index of more than 1000 and with lesser or
 Electron-donor substituent such as methoxy and hydroxyl or no events of dental complications. The compound CH-401 or
electron acceptor such as nitro is essential for biological activity. sodium salt of 3-(3-hydroxy-4-(3-(3-hydroxy-4-methoxyphenyl)
 Nitro group at position 3 and 4 in the A ring and with group 2- propanoyl)phenoxy)propane-1-sulfonic acid (103) is reported
naphthyl at B ring showed significant activity (Fig. 16). to have sweetening power in aqueous solution upto 1000 times
 Chalcone with nitro group at position 4 in the B ring did not (as compared to that of 1% sucrose solution) and persists for a
influence the serum glucose levels. longer period than that of sucrose. In contrast to the sweet taste
 SAR concluded that 3,4-methylenedioxy with a substituent of sucrose, CH-401-Na is perceived at the root of the tongue and
electron-acceptor nitro group in the A or B ring is essential for at both sides of the oral cavity. In lemonades, almost 90% of su-
anti-hyperglycemic activity (Fig. 17). crose may be replaced by CH-401-salts [115]. Various dihy-
 Chloro, bromo, iodo and hydroxyl substitutions at position 2 drochalcone derivatives have been reported as intensive
and iodo substitution at position 3 on A-ring exhibited the highest sweetener where US Patent US5300309 describes neohesperidin
activity compared to pioglitazone and rosiglitazone (Fig. 18). dihydrochalcone (104) having 1800 times sweetening index as
compared to sucrose solution [116] and US Patent US3739064A
2.8. Chalcones as non-nutritive artificial sweeteners described hesperitin dihydrochalcone (105) as potential sweet-
ener [117].
Artificial sweeteners are low-calorie food additives that are
used as substitute of natural sugar [111]. Sugar substitutes proved
862 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865

from diabetic nephrology and markedly attenuated renal injury,

thus may be a novel therapeutic approach for the treatment of
diabetic nephrology [121].

2.9. Miscellaneous chalcones for the treatment of diabetic

nephropathy

Diabetic nephropathy is a major diabetic complication charac- Chalcone derivative L6H21 (107) was reported to ameliorate
terized by the presence of proteinuria (>0.5 g/24 h) or micro the high glucose-mediated inflammation in NRK-52E cells
albuminuria. It is a progressive kidney disease caused by inflam- and attenuate the inflammation mediated renal injury. The
mation of capillaries in the glomeruli (glomerulosclerosis) which compound showed a greater inhibitory effect on expression of
results in increased blood pressure followed by fluid retention pro-inflammatory factors via down-regulation of MAPKs activity
resulting in edema. The treatment intervention includes diminu- in glucose-stimulated renal NRK-52E cells [122].
tion of inflammation in renal region, reduction in macrophage
infiltration, protein restriction, control of hyperglycemia and hy-
pertension (Fig. 19) [118,119]. Phlorizin (106) is an active drug
whose principal pharmacological action is to produce renal
glycosuria and block intestinal glucose absorption through inhibi-
tion of the sodium-glucose symporters located in the proximal
renal tubule and mucosa of the small intestine [120]. Recently,
Phlorizin is reported to prevent diabetic nephropathy by regulating
the expression of a series of proteins involved in renal and uro-
logical diseases, molecular transport, free radical scavenging, and
lipid metabolism. Phlorizin decreased the body weight and serum
concentrations of fasting blood glucose, advanced glycation end
products (AGEs), total cholesterol, triglycerides, blood urea nitro-
gen, creatinine and albumin, which are the chief characteristics of
DM. Morphologic observations showed that phlorizin protects mice

Fig. 19. Chalcones for diabetic nephropathy.

 D.K. Mahapatra et al. / European Journal of Medicinal Chemistry 92 (2015) 839e865 863

3. Patents on anti-diabetic chalcones

Table 1.

Table 1
Patents granted on anti-diabetic chalcones.

S. Citing patent Filing Publication Title Assignee Ref.

No. date date

1. CN103254053A Apr 28, Aug 21, Alpha-fluoro-chalcone type compound and preparation and application Chengdu Institute of Biology, Chinese [106]
2013 2013 thereof Academy of Sciences
2. CN103734842A Dec 18, Apr 23, Angelica keiskei beverage capable of decreasing blood sugar and preparation City College of Zhejiang University [107]
2013 2014 method of Angelica keiskei beverage
3. US7807712B2 Dec 22, Oct 5, 2010 Oxy substituted chalcones as antihyperglycemic and antidyslipidemic agents Ram Pratap et al. [108]
2004
4. US5300309A Mar 18, Apr 5, 1994 Adding low levels of neohesperidin dihydrochalcone to enhance organoleptic Zoster, SA [116]
1993 properties
5. US3739064A Sep 30, Jun 12, Dihydrochalcone sweetening agents Proctor & Gamble [117]
1970 1973

4. Conclusion [14] [Link] (accessed 18.11.14.).

[15] [Link]
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various molecular targets for hypoglycemic activity is highlighted novel chalcone derivatives on a-glucosidase, dipeptidyl peptidase-4, and
in this review. We focused exhaustively on structural aspects with adipocyte differentiation in vitro, BMB Reports.
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the target(s). Chalcones showed their modulatory effect on all T.B. Creczynski-Pasa, R.A. Yunes, J.A. Yunes, A.D. Andricopulo, B.W. Day,
major targets namely PTP1B, PPAR-g, a-glucosidase, DPP-4 and R.J. Nunes, A. Vogt, Cytotoxic 3, 4, 5-trimethoxychalcones as mitotic arresters
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