Therapeutic potential of chalcones as cardiovascular agents Debarshi Kar Mahapatra, Sanjay Kumar Bharti PII: DOI: Reference:

S0024-3205(16)30098-4 doi: 10.1016/j.lfs.2016.02.048 LFS 14733

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Life Sciences

Received date: Revised date: Accepted date:

30 July 2015 21 January 2016 10 February 2016

Please cite this article as: Mahapatra Debarshi Kar, Bharti Sanjay Kumar, Therapeutic potential of chalcones as cardiovascular agents, Life Sciences (2016), doi: 10.1016/j.lfs.2016.02.048

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ACCEPTED MANUSCRIPT Therapeutic Potential of Chalcones as Cardiovascular Agents Debarshi Kar Mahapatra, Sanjay Kumar Bharti*

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Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University),

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Bilaspur - 495009, Chhattisgarh (India)

*Corresponding author

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Dr. Sanjay Kumar Bharti, Institute of Pharmaceutical Sciences,

Bilaspur - 495009, Chhattisgarh (India)

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[email protected]

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Guru Ghasidas Vishwavidyalaya (A Central University),

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ACCEPTED MANUSCRIPT ABSTRACT Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the

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globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3

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million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure

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and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need

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to manage cardiac patient population across the world. Several natural and (semi) synthetic

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chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like Angiotensin Converting Enzyme(ACE), Cholesteryl

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Ester Transfer Protein (CETP), DiacylglycerolAcyltransferase (DGAT), Acyl-coenzyme A:

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cholesterol acyltransferase (ACAT), Pancreatic Lipase (PL), Lipoprotein lipase (LPL), calcium (Ca2+)/potassium (K+) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study

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of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents.

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ACCEPTED MANUSCRIPT Keywords: Chalcones; Cardiovascular; Hematological; Anti-platelet; Anti-obesity; Structure Activity Relationships (SARs)

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ABBREVIATIONS = 1,4-dihydropyridyl

4-HD

= 4-hydroxyderricin

AA

= Arachidonic Acid

ACAT

= Acyl-coenzyme A: cholesterol acyltransferase

ACE

= Angiotensin Converting Enzyme

ADP

= Adenosine 5’-Diphosphate

AngI

= Angiotensin I

AngII

= Angiotensin II

BP

= Blood Pressure

CETP

= Cholesteryl Ester Transfer Protein

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DGAT DRC

= Derricin

ET

= Essential Thrombocythaemia

HC

= Hepatic Cholesterol

HDL

= High-Density Lipoprotein

HFD

= High Fat Diet

HSYA

= Hydroxysafflor Yellow A

HT

= Hypertension

CHD COX-1 CVDs

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1,4-DHP

= Coronary Heart Disease = Cyclooxygenase-1 = Cardiovascular Diseases = Diacylglycerol Acyltransferase

ACCEPTED MANUSCRIPT = Ischemic Heart Diseases

LCC

= Lonchocarpin

LDL

= Low Density Lipoprotein

LPL

= Lipoprotein lipase

MBHC

= Mannich Bases of Heterocyclic Chalcones

MDRC

= Multi-Drug Resistance Channels

MI

= Myocardial Infarction

MTP

= Microsomal Triglyceride Transfer Protein

PE

= Phenylephrine

PLs

= Phospholipids

PL

= Pancreatic Lipase

PPAR

= Peroxisome Proliferator-Activated Receptor

PTX

= Pentoxifylline

SAR

= Structure Activity Relationship

TXA2

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IHD

TXB2

= Thromboxane B2

VLDL

= Very Low Density Lipoprotein

WRP

= Washed Rabbit Platelet

YOH

= Yohimbine

YLSC

= 17-methoxyl-7-hydroxyl-benzofuran chalcone

SHRSP TC TG

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= Stroke-Prone Spontaneously Hypertensive Rats = Total Cholesterol = Triglycerides

= Thromboxane A2

ACCEPTED MANUSCRIPT 1. Introduction Cardiovascular diseases (CVDs) are the leading cause of death across the globe. About

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17.3 million people died from CVDs in 2008 which represents 30% of all global deaths. Of these

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7.3 million people died due to coronary heart disease, 9.4 million deaths were due to high blood pressure and 6.2 million died due to stroke. It is estimated that the death toll may reach 23.3

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million by 2030. Most CVDs are caused by risk factors such as tobacco use, unhealthy diet,

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physical inactivity, high blood pressure, obesity, diabetes and elevated lipids, etc. Lower and middle income countries are disproportionately affected by CVDs (~75%) and death toll occurs

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almost equally in men and women. The reason for reduced CVDs in developed nations may be improved health care facilities and better access to newer drugs [1]. Still, the search for newer

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therapeutic agents with improved pharmacokinetic and pharmacodynamic profile and low toxicity is the foremost need to manage cardiovascular complications.

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Natural products have been reported to exhibit promising therapeutic activities. Various naturally derived scaffolds have gained significant importance in modern day research where more than half of therapeutic agents bear skeletons derived exclusively from nature [2]. Natural products, both in forms of pharmaceuticals and nutraceuticals (or functional foods) are widely accepted across the globe and are considered relatively safe among the majority of population [3]. The natural constituents have been the mainstay of various biological activities, of them, flavonoids class remained the principal candidate. Flavonoids are a group of heterogeneous heat stable polyphenols with various health benefits [4]. There are more than 4000 polyphenolic compounds known in the plant kingdom for over one billion years. They are ubiquitously found in fruits, vegetables, tea, wine, and are usually subdivided into nine sub-classes including flavonols, flavones, flavanones, flavanols, isoflavones, anthocyanidins, proanthocyanidins,

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ACCEPTED MANUSCRIPT aurones and chalcones, which have promising cardioprotective activities [5]. Various studies have suggested that dietary intake of natural flavonoids displayed protective, modulatory, and

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mimetic properties that reduce the risk of atherosclerotic progression, weight control, etc. These

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beneficial effects on the cardiovascular system are exhibited mainly by anti-oxidant activity [6]. Recently, anti-hypertensive, anti-atherosclerotic, anti-platelet, cardioprotective and anti-

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endothelial dysfunction activities have also been identified. Some of the well-known chalcones

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such as tinctormine, lonchocarpin, xanthohumol, xanthohumol B, desmethylxanthohumol, xanthoangelol, xanthoangelol E, isobavachalcone, derricin, safflower yellow, hydroxysafflor

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yellow A, 4-hydroxyderricin, hydroxylated chalcones, substituted chalcone fibrates, sulfonamide substituted chalcones and lupeol-based chalcones etc. have been reported to act on

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cardiovascular targets. A list of chalcones, their cardiovascular targets and physicochemical

2. Chalcone

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properties have been presented in Table 1.

Please Insert Table 1 here

Chalcone (1) or 1,3-diphenyl-2E-propene-1-one is an open chain intermediate in aurones synthesis of flavones that exists in many conjugated forms in nature. They are the precursors of flavonoids and isoflavonoids containing benzylideneacetophenone scaffold, where the two aromatic nuclei are joined by a three carbon α, β unsaturated carbonyl bridge [7]. Kostanecki and Tambor synthesized a series of natural chromophoric products comprising of α, β unsaturated carbonyl bridge and termed them “chalcone” [8]. Chalcones and their derivatives are usually synthesized by Claisen-Schmidt condensation, however, irradiation with domestic microwave is often employed [9]. 6|Page

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Please Insert Structure (1) here

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Chalcones attracted attention among researchers in this century as compared to other

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scaffolds due to its simple chemistry, easy synthetic procedures, multiplicity of substitutions and diverse pharmacological potentials such as MDRC inhibition [10], anti-arrhythmic [11], anti-

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platelet [12], anti-diabetic [13], anti-neoplastic [14], anti-angiogenic [15], anti-retroviral [16],

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anti-inflammatory [17], anti-gout [18], anti-histaminic [19], anti-oxidant [20], anti-obesity [21], hypolipidemic [22], anti-tubercular [23], anti-filarial [24], anti-invasive [25], anti-malarial [26],

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anti-protozoal [27], anti-bacterial [28], anti-fungal [29], anti-ulcer [30], anti-steroidal [31], immunosuppressant [32], hypnotic [33], anxiolytic [34], anti-spasmodic [35], anti-nociceptive

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[36], osteogenic [37], etc.

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3. Molecular targets of chalcone based inhibitors Various chemically diverse chalcone scaffolds have been reported to inhibit various cardiovascular targets such as Angiotensin Converting Enzyme (ACE) [38], calcium/potassium channels [39], TG synthesis [40], Diacylglycerol Acyltransferase (DGAT) [41], Cholesteryl Ester Transfer Protein (CETP) [42], Pancreatic Lipase (PL) [43], Acyl-coenzyme A: cholesterol acyltransferase (ACAT) [44], and Lipoprotein lipase (LPL) [45]. A comprehensive chalconetarget interaction network has been prepared which depicts the therapeutic targets of various chalcones (Figure 1). Many more derivatives are being developed rationally by structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and/or hybridization through conjugation with other pharmacologically active scaffold which showed promising

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ACCEPTED MANUSCRIPT therapeutic potential in the management of hypertension, arrhythmia, thrombosis, obesity and

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Please insert Figure 1 here

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related CVDs.

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4. Chalcones as anti-hypertensive agents

Hypertension (HT) or arterial hypertension is a condition characterized by chronically

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elevated arterial blood pressure (BP). The Hypertension Society has a definite range of BP,

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which is considered normal, beyond that chance of stroke, MI, arrhythmia and related circumstances develop. HT causes severe damage to human body by affecting different organs of

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the body. HT promotes thickening of lamina, hypertrophy of smooth muscles and deposition of

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fibrous tissues in blood vessels. In hypertensive retina, arteriolar thickening, tortuosity and refractiveness occur which eventually results in central retinal vein thrombosis. Hypertensive

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encephalopathy, subarachnoid hemorrhage, etc. are hypertensive complications in CNS [46]. HT is classified into primary and secondary types as per the reason of disease precipitation. The cause of primary HT is still idiopathic, although secondary HT originates from various endocrine and renal disorders [47]. Though both of them can be managed effectively by pharmacotherapy that modulate/block the hypertensive role of α/β receptors, ACE, calcium channels, electrolyte level, etc., but need of safe, long acting, high therapeutic efficacy, multi-targeted and economic depressor agents is the foremost need for cardiac patients. Recently, Chalcone based inhibitors have shown promising activity in the management of arteriolar hypertension. Sherman et al. reported that chalcone R-2803 [2-(2-dimethylaminoethoxy)-3’,4’,5’trimethoxychalcone] (2) displayed effective and long-acting anti-hypertensive agent by inhibiting both norepinephrine and angiotensin induced contractions of isolated aortic muscle in 8|Page

ACCEPTED MANUSCRIPT dogs and rats, when administered i.v. and orally. In the intact animal, R-2803 was essentially devoid of adrenolytic or ganglioplegic activity and it did not possess central hypotensive activity.

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The electrolyte changes in vascular muscle play a role in the initial phase of the hypotensive

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effect of the chalcone [48].

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Please Insert Structure (2) here

Chalcones have been reported to modulate two major anti-hypertensive targets: angiotensin

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converting enzyme (ACE) and calcium channels.

4.1 Chalcones as Angiotensin Converting Enzyme (ACE) inhibitors

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Angiotensinogen is an α-globulin synthesized in the liver and secreted into plasma in large

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concentration when stimulated by corticoids, estrogen, thyroid and other hormones [49]. It is

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cleaved by an aspartyl protease secreted from juxtaglomerular apparatus known as rennin, which forms angiotensin I (AngI). AngI is further cleaved by a membrane bound enzyme on the surface of endothelial cells known as Angiotensin Converting Enzyme (ACE) which converts it into angiotensin II (AngII). The rapid conversion of AngI to AngII in plasma is due to the activity of membrane-bound ACE on the luminal surface of endothelial cells throughout the vasculature [50]. ACE has a large amino terminal extracellular domain, a short carboxyl-terminal intracellular domain, and a 17–amino acid hydrophobic region that anchors the ectoenzyme to the cell membrane. At each step, removal of amino acid occurs from N-peptide terminal [51]. Renin is an important factor which determines the rate of angiotensin II production by hemodynamic, neurogenic and humoral signaling. It is secreted in response to an acute fall in Na+ concentration in distal tube [52]. Angiotensin II production occurs during biochemical cascade which consequentially leads to marked vasoconstriction and aldosterone secretion which 9|Page

ACCEPTED MANUSCRIPT further retains tubular Na+ and ultimately the combined effect results in an increase in blood pressure. Inhibiting this enzyme will lead to failure of conversion of AngI and the pathway get

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terminated [53]. The inhibitors such as captopril, enalapril, etc. bind with zinc atom coupled with

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a proline residue that binds the site on the enzyme which normally accommodates the terminal

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leucine of Angiotensin I (Figure 2).

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Please Insert Figure 2 here

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Bonesi et al .synthesized a series of 3,4,5-trimethoxy chalcones (3-11) and evaluated their Angiotensin-I Converting Enzyme (ACE) inhibitory potential. They reported that

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compound (7) showed the most effective inhibition against the target. Authors concluded that the electron donor group has an inhibiting ability of ACE probably due to free hydroxyl groups of

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phenolic compounds which chelate the zinc ions, thus inactivate the ACE activity. The inhibition of ACE by synthesized molecules may be probably due to the rigid planar structure of the molecule and the presence of hydroxylation in the aromatic ring. Besides appropriate hydroxylation, also a planar structure is indispensable for the metallopeptidases inhibition [10]. A series of 36 novel 2-butyl-4-chloro-1-methylimidazole embedded aryl and heteroaryl derived chalcones have been synthesized and evaluated by Kantevari et al. for ACE inhibitory activity. Compounds (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(5-chlorothiophen2-yl)prop-2-enone

(12),

(E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(1H-pyrrol-2-

yl)prop-2-enone (13) and (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(dibenzo[b,d] thiophen-2-yl)prop-2-enone (14) were the most effective inhibitors based on IC50 value of 3.60, 2.28 and 2.68 μM, respectively. The authors concluded that in natural chalcone (butein), zinc ion

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ACCEPTED MANUSCRIPT coordinates to the carbonyl group of the penultimate peptide bond of the substrate, whereby the carbonyl group becomes polarized and is subjected to nucleophilic attack. Such chelated

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complex of zinc ion in the pocket of ACE inhibits the activity. Since the synthesized new

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chalcones (10-12) also possess structural similarity with natural butein, it is assumed that ACE inhibition may be due to formation of Zn-chelated complex. The increased ACE inhibition for 2-

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butyl-4-chloro-1-methylimidazolechalcones may be due to the increased strength of chelated

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complexes with zinc ions by heterocyclic moieties within the active site of the enzyme, thus inactivating the ACE activity to the greater extent [54].

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Similarly, Bukhari et al. reported the ACE inhibitory potential of a series of newly synthesized 4-diazenylbenzoic acid and pyrimidine based chalcones. All chalcones showed

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effective inhibition of angiotensin converting enzyme, which can be translated for effective control of blood pressure escalation. Compounds (15) and (16) showed the most potent inhibition

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with IC50 values of 0.25 and 0.41 μM, respectively [55]. Safflower yellow (17), extracted from Carthamus tinctorius Linn. has been reported to lower the blood pressure of spontaneously hypertensive rats (SHR). After administration of (17) for five weeks, the plasma renin activity and angiotensin II level diminished in the SHR experimental groups and thus suggested that the decrease of blood pressure is mediated by the renin-angiotensin system [56] (Scheme 1).

Please Insert Scheme 1 here

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ACCEPTED MANUSCRIPT 4.2 Chalcones as calcium channel blocker Ischemic heart disease (IHD), also known as coronary heart disease (CHD) is a class of

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chronic diseases that results from an imbalance between cardiac demand for oxygenated blood

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and its supply. The lumen of coronary artery becomes restricted and is incapable to supply the required amount of nutrients and oxygen to the myocardial cells, thus makes the heart

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“ischemic” (oxygen deficient) [52]. Angina pectoris is one of the prominent syndromes of

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ischemia that affects the majority of the population worldwide. It is treated primarily by a class of agents that vasodilate the veins and decrease venous return to the heart (thus, decreases

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preload) and simultaneously vasodilate arterioles (thus, decreases afterload). The contraction of vascular smooth muscle is mediated by calcium influx. Inhibition of calcium channel influx in

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vascular smooth muscle by channel blockers leads to arteriolar vasodilation [57]. The depolarization and contraction of myocardial cells are mediated by ion influx occur in two major

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phases, where in the former case, fast entry of Na+ ion occurs via fast channels followed by entry of Ca2+ ion through slow channels. The Ca2+ ions trigger contraction by binding with a suppressor element of contraction called troponin and inhibits its function which results in increased interaction of actin and myosin, leading to contractile process. In vascular smooth muscles, calcium induces constriction by binding with a specific intracellular protein calmodulin and forms a complex that begins the contraction process [58]. Inhibition of calcium influx results in inhibition of vascular smooth muscle contraction by depriving the cell from Ca2+ ion. (Figure 3)

Please Insert Figure 3 here

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ACCEPTED MANUSCRIPT Dong et al. designed and synthesized nine hybrid chalcone derivatives conjugated with nitric oxide (NO) donor or 1,4-dihydropyridyl (1,4-DHP) moiety based on molecular

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hybridization strategy. Their vasorelaxant activities were evaluated in aortic rings with

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endothelium pre-contracted with phenylephrine. The authors reported that all of these compounds showed promising vasorelaxant activities. Compounds (18) and (19) exhibited the

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best activity [39]. The 1,4-dihydropyridyl scaffold is a well known anti-hypertensive

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pharmacophore present in calcium channel blockers like amlodipine [59]. The preliminary structure-activity relationships studies revealed that 4-methyl-3-methylene-furoxan moiety was

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the preferable fragment when linked with chalcones, and that the para-hydroxyl group on B-ring of chalcone was the most optimal when conjugated with 1,4-DHP moieties [39].

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In a study, few prenylated and allylated chalcones bearing different substituents were prepared with the aim to discover more potent prenylated chalcones and studied their structure

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activity relationships (SARs). The authors investigated vasorelaxant activities of these chalcones by evaluation in aortic rings with the endothelium pre-contracted by phenylephrine (PE) where they reported that chalcones desmethylxanthohumol (20) & isobavachalcone (21) showed potent relaxant activity. From this study, it was evidenced that the hydroxyl group at the B-ring of chalcones usually resulted in better vasorelaxant activity; substituent pattern and number of hydroxyl groups are other important factors for activities and replacement of prenyl group with allyl group retained the potent activity [60]. A series of chalcone derivatives with strong vasorelaxant activities, mediated via inhibition of calcium influx were identified by Lin et al. Compounds (22-32) showed potent inhibition of calcium mediated contraction of smooth muscle. The authors concluded that 3, 4-

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ACCEPTED MANUSCRIPT dioxygenated group of chalcone might be important in the inhibition of contractions induced by calcium [61].

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Two new quinochalcone C-glycosides, hydroxysafflor yellow A and tinctormine (33) have been isolated from Carthamus tinctorius Linn. by Meselhy et al. which demonstrated

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potent Ca2+ antagonistic action [62] (Scheme 2).

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5. Chalcones as anti-arrhythmic agents

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Please Insert Scheme 2 here

Electrolytes (Na+, Ca2+ and K+) play a vital role in the normal cardiac conduction. Any

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alteration in the normal sequence of electric impulse either from which the impulse originates or conducted through the myocardium causes arrhythmia. Potassium plays pivotal role in cardiac

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physiology. Potassium in extracellular fluids causes the dilation of heart and sluggish the heart rate. Large quantity of potassium have shown to block the proper conduction of cardiac impulse from the atria to the ventricles through the A-V bundle which results in a fall in membrane potential. As the membrane potential decreases, the intensity of the action potential also decreases, which makes contraction of the heart progressively weaker and abnormal rhythm results [63]. The Phase 3 or “rapid repolarization phase” is a stage where L-type Ca2+ current inactivation occurs while the slow delayed rectifying K+ current remained open, which ensures a net outward current corresponding to negative changes in membrane potential which allows more types of K+ channels to open [46]. Few anti-arrhythmic drugs acting on Phase 3 such as bretylium tosylate, amiodarone, ibutilide, and dofetilide cause a prolongation of duration of action potential (QT) which results in prolongation of the effective refractory period and is an

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ACCEPTED MANUSCRIPT effective in paroxysmal supraventricular dysrhythmias [64]. Inhibition of delayed rectifier K+ channel is a very familiar aspect in rational designing of anti-arrhythmic drugs, particularly for

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repolarization inhibitors.

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Yarishkin et al. synthesized nine chalcone derivatives (34-42) having sulfonyloxy group placed on the A-ring (Scheme 3). These compounds showed effective blocking of delayed

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rectifying K+ currents in HEK293 cells. Compound (42) was found to be the most potential K+

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channel inhibitor (IC50 = 0.51 ± 0.05 μM). The authors concluded that activity is a function of structure activity relationships and examined the effect of sulfonation in hydroxyl groups in 4-

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position of both the rings. The study revealed that a dramatic increase in potencies was only observed in case of 4’-sulfonated products. When the effect of sulfonyl substitution on the B-ring

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was studied, 4-sulfonated products proved actually to be slightly less potent than non-sulfonated chalcones. When the effect of hydroxyl groups on the B-ring was examined in non-aminated

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chalcones, a significant decrease in potency was observed when the hydroxy group was removed in the aminated analogues, the potency was increased marginally which suggests that a hydroxy group in the B-ring is not essential. Sulfonate function in the A-ring of the chalcone is a key structural requirement for blocking K+ channels. When the effect of different substituents on the phenyl ring A having sulfonyloxy group was compared, the following potency hierarchy was noted: NH2 (IC50 = 1.1 ±0.1 μM) > CH3 (IC50 = 1.6 ± 0.4 μM) > H (IC50 = 2.4 ± 0.4 μM) > F (IC50 = 2.7 ± 0.4 μM) > NO2 (IC50 = 10.7 ± 1.9 μM). The amino group becomes apparent to be the most favorable substituent for K+ channel blocking activity. This showed that the activity is directly linked to the electron releasing effect of the substituents [11].

Please Insert Scheme 3 here

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ACCEPTED MANUSCRIPT 6. Chalcones as anti-platelet agents Thromboxane synthase (TX) is a cytochrome P450 enzyme that catalyzes the conversion of

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prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a bioactive metabolite of the arachidonic

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acid (AA) which acts as a potent mediator of vasoconstriction, bronchoconstriction and an inducer of platelet aggregation [65]. TXA2 along with pro-aggregatory PGH2 are potent inducer

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of thrombogenesis and play a major role in pathogenesis of myocardial infarction, stroke,

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essential thrombocythemia, disseminated intravascular coagulation and various types of gangrenes. These diseases are primarily characterized by rapid platelet aggregation and thrombus

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formation at the site of vascular damage, which consequently guide to the progression of atherosclerotic plaque formation ensuing restriction of normal blood flow [66]. These situations

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often precipitate ischemic episodes which eventually lead to death, if left untreated. Inhibition of TX results in decreased formation of thromboxane A2 and increase in synthesis of anti-

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aggregatory prostaglandins (PGI2 and PGD2) which leads to reduction in platelet aggregation which consequently reduces the occurrence of myocardial infarction and stroke [67]. Essential Thrombocythaemia (ET) is also a rare clonal stem cell chronic myeloproliferative disorder characterized by overproduction of platelets by megakaryocytes in bone marrow. The most prominent symptom affecting patients involves frequent blood clot formation in the body. The main line of treatment involves prolonging anti-platelet therapy [68]. The endothelial cells of vascular expanse produce and release prostaglandin I2 (PGI2) which facilitates conversion of ATP to cAMP which stimulates platelet aggregation and degranulation. An event of vascular insult results in an activation of Willebrand factor (vWf) that binds to glycoprotein receptor Ib /Ia, thereby activating platelets. The corresponding steps are mediated through GPIIb/IIIa receptors by binding to fibrinogen or vWf, thus leading to cross-linking of

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ACCEPTED MANUSCRIPT platelets to form aggregates. The aggregated mass subsequently degranulates and releases TXA2, ADP, etc., which recruit more candidates at the vascular environment and amplify aggregation

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[69]. Various chalcones find their importance as potential inhibitors of TXA2 and associated

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chemo-attractants which are derived from AA (Figure 4). Various anti-platelet strategies have been recognized which include reversible inhibition of cyclooxygenase-1 (COX-1), ADP-

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induced platelet aggregation, TXA2, arachidonic acid (AA) – induced TXB2 release and other

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miscellaneous mechanisms. Chalcones have been identified to exert anti-platelet potential on

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above targets.

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Please Insert Figure 4 here

Lin et al. evaluated a series of chalcones and reported their potent TXA2 inhibitory

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activity. The compounds (7-11) showed TXA2 inhibitory activity leading to inhibition of platelet aggregation. The authors concluded that ring B of 2’, 5’-dihydroxychalcone substituted by 2furfuryl, 2-thienyl, or 4-fluorophenyl moiety markedly enhances the inhibitory activity [61]. Zhao et al. synthesized a series of trihydroxy chalcones and screened their inhibitory effects in vitro on washed rabbit platelet aggregation induced by arachidonic acid and collagen using aspirin as positive control by Born’s turbidimetric method. The authors identified five compounds (43-47) having potent platelet inhibitory activity, with compound (44) being the most potent. Authors focused on SAR and described that substitution on B ring is essential for anti-platelet activity with methoxy or dimethoxy groups showed the most significant results. Ophenyl methylation or O-allyloxylation at C-4, and demethoxylation at C-3 enhanced the inhibitory effect on arachidonic acid-induced platelet aggregation. Increasing the number of

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ACCEPTED MANUSCRIPT hydroxyl group on chalcone A ring could influence the inhibitory effect on platelet aggregation, but the potency depended on the variation of the substituent of the B ring [12].

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A series of regioisomeric 2-phenyl pyridazin-3-(2H)-ones containing a 3-oxo-3-

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phenylprop-1-en-1-yl fragment at either position 4, 5 or 6 (48-51) and 2-phenyl pyridazin-3(2H)-ones containing the same fragment both at positions 4 and 5 were synthesized. The authors

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concluded that phenyl substituted derivative of each prototype showed the most potent inhibition

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of platelet aggregation compared to methyl substituted as shown by their IC50 values of 3.3±0.4, 17.56±2.01, 11.96±0.68 and 1.98±0.66 μM, respectively [70].

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Two chalcones with the active prenylated group, isobavachalcone (21) and 2’,4’dihydroxy-4-methoxy-3’-prenyldihydrochalcone (52), isolated from Artocarpus lowii King, A.

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scortechinii King and A. teysmanii King were investigated for their ability to inhibit AA, collagen and adenosine diphosphate (ADP)-induced platelet aggregation in human whole blood

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by using an electrical impedance method. Studies revealed that isobavachalcone displayed 38.1% inhibition of AA, 40% inhibition of collagen and 100% inhibition against ADP-induced aggregation of platelet whereas dihydrochalcone showed 30.8% inhibition of AA and 100% inhibition against ADP-induced platelet aggregation [71]. In vitro anti-platelet activity was performed in a series of thiophene/furan based 2’,5’dimethoxy chalcones (53-55) on human washed platelet suspension. Compound (53) exhibited the most potent inhibition of human washed platelet aggregation induced by collagen, significantly inhibited collagen- and AA-induced TXB2 release, and revealed inhibitory effect on COX-1 activity. Molecular docking studies showed that thiophene based chalcones were bound in the active site of COX-1 as confirmed by the DOCK score 4.97, 4.09 and 3.96, respectively.

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ACCEPTED MANUSCRIPT These indicated that the anti-platelet effect of these compounds were mainly mediated through the suppression of COX-1 activity and reduced the thromboxane formation [72].

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A series of 12-O-prenylated, 10-O-allylated chalcones and mannich bases of heterocyclic

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chalcones (MBHC) were screened for in vitro inhibitory effects on aggregation of washed rabbit platelets induced by ADP and collagen. The authors reported that nine compounds (56-64)

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showed 100% inhibition of platelet aggregation. They suggested that the anti-platelet activity

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was governed by the presence of a pyridyl at ring-B and a hydroxy group at position C-3’ in ring-A of the MBHC templates [73].

MA

To identify novel anti-platelet agents, Fujita et al. examined the role of xanthoangelol E (65), isolated from Angelica keiskei Koid. on arachidonic acid metabolism in the gastric antral

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mucosa and platelet of the rabbit. This compound effectively inhibited the production of TXB2 and 12-hydroxy-5,8,10-heptadecatrienoic acid from exogenous arachidonic acid in

AC CE P

platelets with IC50 values of approximately 5 μM. The formation of 12-hydroxy-5,8,10,14eicosatetraenoic acid was also reduced by this compound (IC50 of 50 μM). These results suggest that xanthoangelol E has the potential to modulate arachidonic acid metabolism in platelets [74]. In a recent study, antagonistic effect of hydroxysafflor yellow A (HSYA) (66) on washed rabbit platelet (WRP) aggregation

and rabbit polymorphonuclear

leukocytes (PMNs)

aggregation induced by platelet activating factor (PAF) was examined by in vitro turbidimetric assay. The authors also studied the PAF receptor antagonistic effect of HSYA by using radio ligand binding assay (RLBA). The authors concluded that specific binding inhibitory effect was found to be concentration-dependent. The IC50 value of HSYA to inhibit WRP aggregation and rabbit PMN aggregation was 0.99 and 0.7 mmol/L, respectively [75].

19 | P a g e

ACCEPTED MANUSCRIPT Fontenele et al. studied the effects of two chalcones namely; lonchocarpin (LCC) (67) and derricin (DRC) (68) isolated from the hexane fraction of roots from Lonchocarpus sericeus

PT

Poir. Kunth (Fabaceae) on human platelet aggregation induced by a variety of agonists. Authors

RI

reported that LCC and DRC significantly inhibited adenosine 5’-diphosphate (ADP)-, arachidonic acid (AA)-, thrombin (THR)-, collagen (COL)-, and adrenalin (ADR)-induced

SC

aggregation in a dose-dependent manner. They suggested that the anti-platelet effect of LCC and

NU

DRC may be mediated mainly by the inhibition of phosphodiesterase activity or elevation of adenosine 3’,5’-cyclic monophosphate (cAMP) and guanosine 3’:5’-cyclic monophosphate

MA

(cGMP) intracellular levels or even by inhibition of TX formation, as these two substances inhibited the aggregation induced by AA, COL, and THR. The authors also studied the

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synergistic effect of LCC or DRC to pentoxifylline (PTX), a known phosphodiesterase inhibitor and reported that it caused a significant potentiation of platelet inhibition (41.1% and 47.4%)

AC CE P

when compared with LCC (20.3%) or DRC (17.9%) alone, whereas, addition of aspirin or yohimbine (YOH) to LCC or DRC did not change their effects on platelet aggregation induced by AA or ADR [76].

Qin et al. investigated the inhibitory effects of 17-methoxyl-7-hydroxyl-benzofuran chalcone (YLSC) (69) on platelet aggregation induced by ADP, collagen and AA in three dosage groups of rat (2.5, 5 and 10 mg/kg) and reported that YLSC could significantly inhibit platelet aggregation induced by ADP and collagen, but did not inhibit platelet aggregation induced by AA [77]. Ko et al. developed few chalcone-based anti-platelet compounds with anti-inflammatory action. These compounds were evaluated on washed rabbit platelets and human platelet-rich plasma and reported that both arachidonic acid-induced platelet aggregation and collagen-

20 | P a g e

ACCEPTED MANUSCRIPT induced platelet aggregation was potently inhibited by almost all the chalcone derivatives. Compounds (70), (71) and (74) significantly inhibited the aggregation of washed rabbit platelets

PT

induced by platelet-activating factor by 2.8±2.2, 4.0±3.2 and 0 %, respectively. Compounds (72-

RI

74) showed significant inhibition of secondary aggregation induced by adrenaline as indicated by the percentage platelet aggregation result; 42.6±8.0, 48.8±7.3 and 36.5±4.0, respectively. The

SC

authors concluded that the anti-platelet effect of (72-74) is mainly mediated through inhibition of

NU

COX-1 or reduced thromboxane formation or owing to the inhibition of TX. The inhibitory effect of (70), (71) and (74) on platelet aggregation induced by platelet-activating factor could be

MA

owing to calcium antagonizing effect or inhibition of intracellular calcium mobilization [78]

D

(Scheme 4).

AC CE P

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Please Insert Scheme 4 here

7. Chalcones for the management of hyperlipidemia Atheromatous plaques are focal lesions of large and medium sized arteries that are rich in both extracellular and intracellular cholesterol. Initially, fatty streaks start depositing into the vascular lumen which progresses to develop fibro-fatty growths that can protrude into the lumen and subsequently minimizes the blood flow. In the beginning few symptoms are observed, but as they progress these conditions precipitate angina pectoris. This situation triggers thrombosisplatelet-fibrin-thrombi propagation which occludes the artery causing myocardial infarction (MI) or stroke. Recent studies have shown a strong relationship between the concentration of circulating lipid fragments and the risk of atheroma [79]. Recently, few chalcone-based products have come into market for treating hyperlipidemia. Patent US 2007/0218155 A1 described such product for treating hypercholesterolemia and heart disease [80]. A large number of therapeutic 21 | P a g e

ACCEPTED MANUSCRIPT targets such as DGAT, LPL, PL, CETP, and PPAR-α have been identified which are directly

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7.1 Chalcones as inhibitors of triglyceride (TG) synthesis

PT

associated with lipid synthesis, transfer and metabolism.

SC

Triglycerides (TGs) are a mainstream component of all dietary fats in the human body. TGs

NU

are absorbed from the small intestine and get transported into tissues where they are stored as fat. Fats are vital components which provide a source of energy. Triacylglycerol (TAG) gets

MA

synthesized in cytosol of adipose cells from glycerol-3-phosphate and Acyl-CoA in the presence of DGAT [81]. High blood triglyceride level often occurs due to increased lipolysis, which

D

consequently increases the risk of atherosclerosis that subsequently progresses to coronary heart

TE

diseases. This risk is further amplified by the presence of risk factors such as smoking, elevated

AC CE P

blood cholesterol level, high blood pressure, obesity, lifestyle and to some extent mental state. A clear correlation has been reported between serum triglyceride level and obesity. With an increase in serum triglyceride level, a sharp elevation in obesity has been observed and viceversa [82].

Casaschi et al. examined the role of xanthohumol (XN) (75), a plant chalcone, on apolipoprotein B (apoB) and triglyceride (TG) synthesis and secretion, using HepG2 cells as the model system. The authors reported that XN decreased apoB secretion in a dose-dependent manner under both basal and lipid-rich conditions (upto 43%). This decrease was associated with increased cellular apoB degradation and inhibition of TG synthesis in the microsomal membrane and the transfer of this newly synthesized TG to the microsomal lumen (decrease in 26 and 64%, respectively, under lipid-rich conditions), which indicates that TG availability is a determining

22 | P a g e

ACCEPTED MANUSCRIPT factor in the regulation of apoB secretion under the experimental conditions. The inhibition of TG synthesis was caused by a reduction in diacylglycerol acyltransferase (DGAT) activity,

PT

which corresponded to a decrease in DGAT-1 mRNA expression. Microsomal triglyceride

RI

transfer protein (MTP) may also control the rate of TG transfer from the microsomal membrane to the active luminal pool. XN decreased MTP activity in a dose-dependent manner (upto 30%)

SC

[40] (Figure 5).

MA

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Please insert Figure 5 here

7.2 Chalcones as Diacylglycerol Acyltransferase (DGAT) inhibitors

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Diacylglycerol acyltransferase (DGAT) is an enzyme that catalyzes the formation

TE

of triglycerides from diacylglycerol and Acyl-CoA. The reaction catalyzed by DGAT is

AC CE P

considered the terminal and only committed step in triglyceride synthesis and to be essential for the formation of adipose tissue [83]. In the small intestine, DGAT is required for the absorption of dietary TGs, in liver, DGAT plays a significant role in synthesizing TGs from either fatty acids synthesized de novo or from fatty acids taken up from the circulation. Adipose tissues serve as the store house of TGs. DGAT plays a pivotal role in re-esterification of TGs and their cytosolic storage [84]. Inhibition of DGAT leads to reduced formation and absorption of TGs, thus is a major anti-obesity target. Xanthohumol (75) and xanthohumol B (76) were isolated from methanol extract of hops of Humulus lupulus Linn. These chalcones inhibited the DGAT activity with IC50 values of 50.3 and 194.0 μM in rat liver microsomes, respectively. They showed preferential inhibition of triacylglycerol formation in intact Raji cells, indicating that they inhibit DGAT activity preferentially in living cells [41] (Scheme 5).

23 | P a g e

ACCEPTED MANUSCRIPT Please Insert Scheme 5 here

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7.3 Chalcones as Cholesteryl Ester Transfer Protein (CETP) inhibitors Cholesteryl ester transfer protein (CETP) is a plasma protein that facilitates transfer of

RI

cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from VLDL

SC

or LDL and exchanges them for cholesteryl esters from HDL [85]. Inhibition of CETP leads to

NU

an increase in the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apoB [86]. High density lipoprotein (HDL)-cholesterol levels are correlated with a low risk

MA

of atherosclerosis. The inhibition of CETP leads to an increase in HDL-cholesterol and is expected to be the promising anti-atherogenic target.

D

Hirata et al. investigated the inhibitory activity of various chalcones: xanthohumol,

TE

desmethylxanthohumol, trans-chalcone, isoliquiritigenin, cardamonin, naringenin chalcone and

AC CE P

phloretin. The authors reported that xanthohumol (75) showed the highest inhibition of CETP with IC50 value of 88.0 μM. Naringenin chalcone showed weak CETP inhibition compared with xanthohumol. These results suggested that the prenyl group at the A-ring of xanthohumol was the essential feature for its CETP inhibitory activity. Naringenin chalcone and phloretin had the same level of CETP inhibitory activity, suggesting that the α,β-unsaturated ketone of chalcone was not required. The 6’-methoxy group of xanthohumol seemed to be too bulky for CETP inhibition since desmethylxanthohumol, the biosynthetic precursor of xanthohumol showed potent CETP inhibition compared to xanthohumol. In addition, isoliquiritigenin showed potent CETP activity compared to naringenin chalcone and cardamonin, suggesting that the functional group at 6’-position might not be essential for CETP inhibition or it may sterically hinder the binding of chalcones to CETP. However, requirement for the 6’ functional group remains controversial since naringenin chalcone and cardamonin showed the same level of inhibitory 24 | P a g e

ACCEPTED MANUSCRIPT activity. Based on the comparison between cardamonin and trans-chalcone, it was found that 2’,4’-hydroxy group is essential for CETP inhibition. These results suggest that the chalcone

PT

scaffold and 3’-prenyl group of xanthohumol is responsible for the CETP inhibitory activity

RI

whereas the 6’-methoxy group might be unfavorable for its inhibitory activity and the α,β-

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7.4 Chalcones as Pancreatic Lipase (PL) inhibitors

SC

unsaturated keto did not have any effect on its inhibitory activity [42].

MA

Pancreatic lipase (PL) is a lipolytic enzyme secreted from the pancreas that breaks fat in the body by hydrolyzing the ester linkages of triglyceride substances into monoglycerides and free

D

fatty acids, thereby plays a key role in dietary fat absorption. Inhibition of pancreatic lipase leads

TE

to decreased absorption of dietary triglycerides from intestine [87]. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and are

AC CE P

excreted undigested.

Birari et al. studied the effect of hydroxylated chalcones and their di-glycosides isolated from Glycyrrhiza glabra Linn. roots on in vitro PL inhibitory activity. Both chalcones and their glycosidic hybrids (77-80) showed strong inhibition against PL with IC50 values of 7.3, 35.5, 14.9 and 37.6 μM, respectively. Docking analysis showed a high binding potential of compound (77) towards the active site of PL with total docking score of −23.7 kcal/mol. The docking score of other compounds (78-80) along with the hydrogen bonding interaction residues were determined. In human PL, N-terminal domain residues Ser152, Asp176, and His263 form the catalytic triad while C-terminal domain binds to co-lipase, the cofactor required for the activity. Within the PL enzyme active site, it was clearly observed that the compound (77) formed strong hydrogen bonding interactions with the active site amino acid residues of the enzyme. The 25 | P a g e

ACCEPTED MANUSCRIPT compounds binding to these catalytic and other nearby residues are expected to play an important role in PL inhibition. The authors reported that in silico ADME analysis revealed that compound

PT

(77) showed good oral bioavailability. Its diglycoside, licuroside (79), having sugar linked in 4-

RI

position also strongly inhibited PL in vitro, which modulates ADME profile by its glycone moiety. This indicates that chemical modifications of compound (77) may provide stronger PL

SC

inhibitor with necessary pharmacokinetic properties. They also investigated the anti-obesity and

NU

lipid lowering potentials of (77) and (79) in high fat diet (HFD) fed male SD rats. They reported that in rats supplemented with compound (77), the body weight increased only 23.2±3.6 g as

MA

compared to 64.2±0.5 g in the HFD control group while in the rats treated with compound (79) showed 28.2±1.6 g weight gain only. Compound (77) decreased the levels of plasma total

TE

D

cholesterol (TC) to 84.6±1.4 mg/dl and plasma TG to 128.8±6.0 mg/dl. Compound (79) also lowered the plasma TC and TG levels considerably. The potential of the chalcone scaffold as a

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source of PL inhibitors for preventing obesity is thereby justified [21]. Nguyen et al. performed molecular docking studies of sixty-six chalcones using FlexX software integrated in LeadIT, synthesized six biologically potential derivatives and evaluated for their PL inhibitory activities. Three compounds (81-83) showed the best binding with the enzyme (IC50 CH3 > H > F > NO2. Substitution of sulfonate (NH2-C6H5-

TE

SO2-) group at 4-position (IC50 = 0.51 μM) increases the potency by two times than at 3-



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position (IC50 = 1.1 μM).

Aryloxybutyric acid (fibric acid derivatives or fibrates) group at 4-position of A-ring is vital for LPL activation. Presence of the bicyclic ring in the B-ring may play an imperative role in LPL activation.



Prenyl group is a critical factor in designing modulators acting on diverse antihyperlipidemic targets. Prenyl group takes part in binding with the active site. Prenylation at 3-position of A-ring resulted in effective fabrication of DGAT, ACAT and CETP inhibitors. Replacement of prenyl group by a heterocyclic scaffold result in drastic fall in potency against DGAT.



3, 4, and 5-trimethoxy substitution plays pivotal role in ACE inhibition.



2, 4-dihydroxy substitution at A-ring and 3- or 4-hydroxy substitution at B-ring is essential for PL inhibition. Presence of glycon moiety at B-ring has both

33 | P a g e

ACCEPTED MANUSCRIPT pharmacodynamic and pharmacokinetic importance in PL inhibition. Carbonyl group in chalcone structure is important for its bonding to amino acids. Five or six membered heterocycles (thiophene, furan, and pyridine) in B-ring play key

PT



RI

role in anti-platelet activity. In six membered B ring, substitution at 3- or 4-position with methoxy/hydroxy or dimethoxy/dihydroxy groups showed the most significant results for

SC

anti-platelet activity. Substitution of A ring by 2,4,6-trihydroxy or 2, 5-dihydroxy groups

NU

has a noteworthy role in inhibition. O-phenyl methylation or O-allyloxylation at C-4, and demethoxylation at C-3 enhanced the inhibitory effect on arachidonic acid-induced

MA

platelet aggregation.

Conclusion

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Please insert Figure 6 here

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The present review highlights the chalcones acting on molecular targets, namely ACE, calcium channel, potassium channel, CETP, AGAT, DGAT, PL and platelets etc. as potential cardiovascular agents. They showed promising activity and are deserving candidates for the management of cardiovascular diseases such as hypertension, arrhythmia and associated hematological complications. Various natural, (semi) synthetic heterocyclic methoxy substituted chalcone derivatives demonstrated their prospective as anti-platelet agents for cardiovascular disorders like stroke, MI and ET. Several chalcones containing 1,4-dihydropyridine, prenyl, sulfonamide, glycone and/or fibrate moiety in their structures showed inhibition of various molecular targets. 1,4-dihydropyridine, a prominent scaffold of calcium channel blockers like nifedipine, amlodipine when coupled with chalcone, showed better inhibition of calcium channels. Similarly, sulfonamide-chalcone hybrids showed their importance as anti-arrhythmic

34 | P a g e

ACCEPTED MANUSCRIPT agents by inhibiting delayed rectifier channels. The prenylated hybrids have also shown better pharmacokinetics as well as pharmacodynamic profile compared to standard marketed drugs.

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The prenylated chalcones such as xanthohumol, isobavachalcone, xanthoangelol, 4-

RI

hydroxyderricin and 2’,4’-dihydroxy-4-methoxy-3’-prenyldihydrochalcone showed inhibition of AA, CETP, DGAT and exhibited anti-obesity potential. Still, none of them gained adequate

SC

attention in contemporary medicine and need to be explored properly as potential therapeutic

NU

agents for cardiovascular disorders. Synthetic analogs having natural chalcone scaffold in their structures may have fewer side effects compared to purely synthetic drugs. The compounds

MA

having promising activity, well defined mechanism of actions, and SARs must be considered as a strong prototype to design and develop novel and more effective chalcone based inhibitors for

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D

the management of cardiovascular disorders.

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TE

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Evaluation of Chalcones and Analogues as Hypolipidemic Agents, Arch. Pharm. Chem. Life Sci. 339 (2006) 541–546.

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PT

Science & Business Media, 2011.

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[104] J. Buckingham, V.R.N. Munasinghe, Dictionary of Flavonoids with CD-ROM, first ed., CRC Press, 2015.

SC

[105] S. Yannai, Dictionary of Food Compounds with CD-ROM, second ed., CRC Press, 2012.

NU

[106] Atta-ur-Rahman, Studies in Natural Products Chemistry: Bioactive Natural Products, first ed., Elsevier, Philadelphia, 2005. Combined

Chemical

Dictionary

MA

[107]

http://ccd.chemnetbase.com/dictionary-

AC CE P

TE

D

search.do?method=view&id=11447924&si (Accessed on January 13, 2016)

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ACCEPTED MANUSCRIPT FIGURE LEGENDS Figure 1. Chalcone-target interaction network.

PT

The drug-target network was generated from the associations between cardiovascular chalcones and their target proteins. The network signifies a linkage between drugs (described as circles) and known molecular

RI

targets such as enzymes, proteins, ionic channels, etc. (represented as rectangles). [Courtesy: Li et al.

SC

BMC Systems Biology 8 (2014) 141-153]

NU

Figure 2. Angiotensin Converting Enzyme (ACE) as molecular target of chalcones. Angiotensinogen is cleaved by renin to form AngI, which was further cleaved by ACE to form AngII.

MA

AngII production leads to marked vasoconstriction and aldosterone secretion which retains tubular Na+ and in addition results in an increased blood pressure. Inhibiting ACE by chalcones (11), (12) and (15)

D

leads to failure of conversion of AngI and the pathway get terminated, resulting effective check on

TE

hypertension.

AC CE P

Figure 3. Calcium channel inhibition by chalcone derivatives. Lumen of coronary arteries become restricted and is incapable to supply the required amount of nutrients and oxygen to the myocardial cells, precipitating angina. Further, contraction of vascular smooth muscle mediated by calcium influx leads to spasm and aggravates the condition. Chalcones (20), (21), and (32) showed potent inhibition of calcium channel influx in vascular smooth muscle leading to arteriolar vasodilation.

Figure 4. Anti-platelet targets of chalcone derivatives. TX converts PGH2 to TXA2 which acts as a potent inducer of platelet aggregation. Along with several pro-aggregatory like COX-1, AA, PGI2 and PGD2, thrombi formation results in MI, stroke conditions, where atherosclerotic plaques formation restricts the normal blood flow. Chalcones (44), (52) and (54) cause reversible inhibition of COX-1, TXA2, AA leads to reduction in platelet aggregation.

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ACCEPTED MANUSCRIPT Figure 5. Anti-hyperlipidemic targets of xanthohumol. ApoB is the primary component of every lipoprotein (chylomicrons, VLDL, and LDL). DGAT catalyzes

PT

the formation of TG. MTP promotes TG transfer from the microsomal membrane to luminal pool. A high blood TG level consequently increases the risk of atherosclerosis that progresses to coronary heart

RI

diseases. Xanthohumol (75) decreases apoB secretion, increases cellular apoB degradation, inhibits TG

NU

collectively exhibit anti- hyperlipidemic effect in body.

AC CE P

TE

D

MA

Figure 6. SARs of chalcone derivatives.

50 | P a g e

SC

synthesis in the microsomal membrane, reduces DGAT activity and decreases MTP activity, which

ACCEPTED MANUSCRIPT SCHEME LEGENDS Scheme 1. List of chalcones as ACE inhibitors.

RI

Scheme 4. List of chalcones as anti-platelet agents.

SC

Scheme 3. List of chalcones as anti-arrhythmic agents.

PT

Scheme 2. List of chalcones as calcium channel blockers.

NU

Scheme 5. List of chalcones as Diacylglycerol Acyltransferase (DGAT) inhibitors.

MA

Scheme 6. List of chalcones as Pancreatic Lipase (PL) inhibitors. Scheme 7. List of chalcones as Lipoprotein Lipase (LPL) activators.

D

Scheme 8. List of miscellaneous anti-hyperlipidemic chalcones.

AC CE P

TE

Scheme 9. List of miscellaneous chalcones with cardiovascular activity.

51 | P a g e

ACCEPTED MANUSCRIPT Active place for substitution O

3'

A

4'

2

1' 6'

1 6

B

3 4

5

Primed

Unprimed

SC

(1)

RI

5'

PT

2'

AC CE P

TE

D

MA

NU

(General structure of chalcone)

52 | P a g e

ACCEPTED MANUSCRIPT

O

O

N

H3CO

PT

H3CO OCH3

AC CE P

TE

D

MA

NU

SC

RI

(2)

53 | P a g e

ACCEPTED MANUSCRIPT O H3CO H3CO

R1 R2

PT

OCH3

RI

(3) R1 = R2 = H (4) R1 = H, R2 = OCH3 (5) R1 = OCH3, R2 = H (6) R1= OCH3, R2 = OH

SC

(7) R4 = OH, R2 = OCH3 (8) R1 = OCH3, R2 = NO2 (9) R1 = OCH3, R2 = NH2 (10) R1 = NO2, R2 = OH (11) R1 = OCH3, R2 = F CH3 N

NU

O R

N

MA

Cl

Cl

HN

D

S

(13) R =

S

(14) R =

TE

(12) R =

OH

AC CE P

O

N N

HO

OH

O

R

(15) R = OCH3 (16) R = OH

HO HO

HO

O HO

O

O

OH

HO HO

OH

OH O

HO

O

O

O O

OH

OH

O

(17) Scheme 1. List of chalcones as ACE inhibitors 54 | P a g e

OH

ACCEPTED MANUSCRIPT HO NO2 N N

HO

O O

O

N H

O OH O

OH

OH

SC

1,4-dihydropyridyl Scaffold

OH

HO

D

OH

MA

Prenyl group

AC CE P

(20)

OH

OH

OH O

TE

OH O

(19)

NU

(18)

HO

O

O

RI

O

O

O

PT

O

O

(21)

R4 R5

R3

R2 R1

O

(22) R1 = R2 = R3 = H, R4 = R5 = OH (23) R1 = R2 = R3 = R4 = H, R5 = OH (24) R1 = R4 = OH, R2 = R3 = R5 = H (25) R1 = H, R2 = OH, R4 = R5 = OCH3 (26) R1 = R3 = H, R2 = R4 = R5 = OH (27) R1 = R3 = OH, R2 =H, R4 = R5 = OCH3 (28) R1 =R3 = OH, R2 = R4 = H, R5 = F (29) R1 = R3 = OH, R2 =R4 = H, R5 = Cl

55 | P a g e

ACCEPTED MANUSCRIPT OH

X

OH O

OH O

(32)

HO

OH OH OH OH

MA

H2 HO C

O OH C

H N

OH

NU

H2 HO C

SC

RI

(30) X = S; (31) X = O

PT

OH

OH

OH

O

O

TE

D

(33)

AC CE P

Scheme 2. List of chalcones as calcium channel blockers.

56 | P a g e

ACCEPTED MANUSCRIPT O O S O O

R2

PT

R1

RI

(34) R1 = H, R2 = OH (35) R1 = CH3, R2 = OH (36) R1 = CH3, R2 = OCH3 (37) R1 = F, R2 = OH

SC

(38) R1 = NO2, R2 = OH (39) R1 = NH2, R2 = OH (40) R1 = NH2, R2 = H

MA

O S O O

NU

(41) R1 = NHAc, R2 = OH

O

OH

D

H2N

TE

Sulfonate group

(42)

AC CE P

Scheme 3. List of chalcones as anti-arrhythmic agents.

57 | P a g e

ACCEPTED MANUSCRIPT R2 OH

R1

PT

HO

OH O

RI

(43) R1 = OCH3, R2 = OCH2C6H5 (44) R1 = R2 = OCH3 (45) R1 = OCH3, R2 = OCH2CHCH2

SC

(46) R1 = H, R2 = OCH3 (47) R1 = H, R2 = Cl

O O

NU

4

N N

5

R

Ph Ph O

(51)

TE

D

(48) R = 4-Position (49) R = 5-Position (50) R = 6-Position

O

N N

MA

6

O

HO

AC CE P

OH

OCH3

OCH3 S

R1 S

R2

OH O

H3CO

(52)

H3CO

O

(53)

O

(54) R1 = R2 = H (55) R1 = H, R2 = CH3

R1 H3CO R2

N OH O

O

(56) R1=

58 | P a g e

N

O

, R2 = H

(57) R1 = H, R2 =

N

ACCEPTED MANUSCRIPT OH N O

R

PT

O

RI

(58) R =2-pyridyl (59) R =3-pyridyl (60) R = 4-pyridyl

N

O

N

MA

O

AC CE P

TE

D

(61)

OH

OH

O

N

(62) R = 2-thiophene (63) R = 2-furan (64) R = 3-pyridyl

HO

OH

OH O

HO

OH

OH

HO

OH

(66)

H3CO

O

OH O

(67)

OH

O

HO

(65)

59 | P a g e

O

O HO HO

O

O HO H3CO

OCH3

R

N

NU

OH

SC

O

OH O

(68)

ACCEPTED MANUSCRIPT O

O

H3CO OH

PT

OH O

(70) R = CH3 (71) R = Cl

RI

(69)

SC

OH OH

OH

NU

S

MA

O

(72)

D TE AC CE P

R

OH O

(73) R = H (74) R = Cl

Scheme 4. List of chalcones as anti-platelet agents.

60 | P a g e

R

OCH3

ACCEPTED MANUSCRIPT Essential portion for binding OH OH

O

OH

O

H3CO

PT

H3CO

OH

RI

HO

OH

SC

(75)

O

(76)

AC CE P

TE

D

MA

NU

Scheme 5. List of chalcones as Diacylglycerol Acyltransferase (DGAT) inhibitors.

61 | P a g e

ACCEPTED MANUSCRIPT OH

OH

OH

OH

OH

OH OCH3

PT

OH O

O

(78)

RI

(77)

SC

OH O

HO HO

NU

O O O OH

MA

HO HO OH

OH

Glycone moiety

OH

OH

OH O

(80)

AC CE P

TE

(79)

O

O

D

OH O

HO HO

HO

OH O R1 R2

(81) R1 = OH, R2 = H (82) R1 = R2 = OCH3 (83) R1 = H, R2 = OH

Scheme 6. List of chalcones as Pancreatic Lipase (PL) inhibitors.

62 | P a g e

ACCEPTED MANUSCRIPT O O

O

H3C

O X

O

C2H5

O

NH

RI

O

R

PT

O

NH

(85) R = H, X = -CH2(CH2)2

SC

(84)

NU

(86) R = CH3, X = -C(CH3)2

O

O O

O

O

O

NO2 O

O

Fibrate

TE

D

OH

MA

CH3

OCH(CH3)COOH

(88)

AC CE P

(87)

O

O

O

Chalcone R

O

O

O Lupeol

EtO

(89)

(90) R = OCH3 (91) R = Br (92) R = NO2

Scheme 7. List of chalcones as Lipoprotein Lipase (LPL) activators.

63 | P a g e

ACCEPTED MANUSCRIPT OH O

R2

OH

PT

R1

R1

Br

R2

NU

Br

SC

O

RI

(93) R1 = OCH3, R2 = H (94) R1 = OH, R2 = OCH3

MA

(95) R1 = R2 = 4-Cl (96) R1 = 4-Cl, R2 = H (97) R1 = 3,4-Cl, R2 = 4-Cl

AC CE P

TE

D

Scheme 8. List of miscellaneous anti-hyperlipidemic chalcones.

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ACCEPTED MANUSCRIPT OH O H3CO

OH

O

HO

OH

OCH3

PT

OH

(99)

RI

(98)

OH O

O

H3CO

SC

H3CO

OH

NU

CHO

OCH3 OH

D

O

OH

AC CE P

(102)

OH O

HO

OH

TE

HO

O

H3CO

(104)

OH

(101)

MA

(100)

HO

(103)

R

O

OCH3

OCH3

HO

OH

OH

(105) R = H (106) R = OH

Scheme 9. List of miscellaneous chalcones with cardiovascular activity.

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AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Figure 1. Chalcone-target interaction network. The drug-target network was generated from the associations between cardiovascular chalcones and their target proteins. The network signifies a linkage between drugs (described as circles) and known molecular targets such as enzymes, proteins, ionic channels, etc. (represented as rectangles). [Courtesy: Li et al. BMC Systems Biology 8 (2014) 141-153]

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AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Figure 2. Angiotensin Converting Enzyme (ACE) as molecular target of chalcones. Angiotensinogen is cleaved by renin to form AngI, which was further cleaved by ACE to form AngII. AngII production leads to marked vasoconstriction and aldosterone secretion which retains tubular Na+ and in addition results in an increased blood pressure. Inhibiting ACE by chalcones (11), (12) and (15) leads to failure of conversion of AngI and the pathway get terminated, resulting effective check on hypertension.

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AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Figure 3. Calcium channel inhibition by chalcone derivatives. Lumen of coronary arteries become restricted and is incapable to supply the required amount of nutrients and oxygen to the myocardial cells, precipitating angina. Further, contraction of vascular smooth muscle mediated by calcium influx leads to spasm and aggravates the condition. Chalcones (20), (21), and (32) showed potent inhibition of calcium channel influx in vascular smooth muscle leading to arteriolar vasodilation.

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AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Figure 4. Anti-platelet targets of chalcone derivatives. TX converts PGH2 to TXA2 which acts as a potent inducer of platelet aggregation. Along with several pro-aggregatory like COX-1, AA, PGI2 and PGD2, thrombi formation results in MI, stroke conditions, where atherosclerotic plaques formation restricts the normal blood flow. Chalcones (44), (52) and (54) cause reversible inhibition of COX-1, TXA2, AA leads to reduction in platelet aggregation.

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AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Figure 5. Anti-hyperlipidemic targets of xanthohumol. ApoB is the primary component of every lipoprotein (chylomicrons, VLDL, and LDL). DGAT catalyzes the formation of TG. MTP promotes TG transfer from the microsomal membrane to luminal pool. A high blood TG level consequently increases the risk of atherosclerosis that progresses to coronary heart diseases. Xanthohumol (75) decreases apoB secretion, increases cellular apoB degradation, inhibits TG synthesis in the microsomal membrane, reduces DGAT activity and decreases MTP activity, which collectively exhibit anti- hyperlipidemic effect in body.

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NU

SC

RI

PT

ACCEPTED MANUSCRIPT

AC CE P

TE

D

MA

Figure 6. SARs of chalcone derivatives.

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ACCEPTED MANUSCRIPT Table 1. Chalcones, their cardiovascular targets and physicochemical properties. Physicochemical IC50

Targets / Inhibits

properties

(μM)

inhibiting both NA

m.p. 331-333°C,

NA

48

dimethylaminoethoxy)-

and angiotensin

log P 3.08

3’,4’,5’-

induced

trimethoxychalcone]

contractions of

(2)

aortic muscle

2.28-3.6

54

NA

56, 103

2.9

39

0.85

60, 105

No.

MA

2. (E)-3-(2-butyl-4-

ACE inhibition

AC CE P

3. Safflower yellow (17)

136°C, 120°C

TE

imidazol-5-yl)-1-

enone (12-14)

m.p. 96°C,

D

chloro-1-methyl-1H-

(substituted)-prop-2-

Reference

NU

1. R-2803 [2-(2-

PT

Molecular

RI

Chalcones

SC

S.

ACE inhibition

Yellow to dark brown crystals, paste or powder with faint characteristic odor, very soluble in water

4. 1,4-dihydropyridyl linked chalcone (19)

Calcium channel

Pale yellow

inhibition

solid, 172-174°C

5. Desmethylxanthohumol inhibition of 72 | P a g e

Orange solid,

ACCEPTED MANUSCRIPT

Yellow

ACAT

44, 60, 71,

inhibition of

crystalline in

(48),

104

calcium influx,

nature, m.p. 166-

Ca2+

inhibit AA and

167°C, λmax 310

influx

ADP-induced

aggregation

Calcium channel

Yellow

inhibition

amorphous

Sulfonate substituted

Blocks delayed

AC CE P

8.

TE

D

MA

7. Tinctormine (33)

chalcones (42)

nm

NU

platelet

PT

ACAT inhibition,

SC

6. Isobavachalcone (21)

RI

calcium influx

(20)

(10.2), ADP (58.1) 10

62, 104

0.51-

11

powder, λmax 275, [α]D 260 m.p. 81-82°C

rectifying K+

10.7

currents in HEK293 cells

9. 2-phenyl pyridazin-3-

m.p. 156-157°C,

1.98-

(2H)-ones containing 3- activity by COX-1

175-177°C, 119-

11.96

oxo-3-phenylprop-1-en- inhibition

120°C, 192-

1-yl fragment (48-51)

194°C

10. 2’,4’-dihydroxy-4-

Anti-platelet

inhibit AA and

Pale yellow

ADP

methoxy-3’-

ADP-induced

powder, m.p.

(41.4)

prenyldihydrochalcone

platelet

91.1-92.3°C, λmax

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70

71, 107

ACCEPTED MANUSCRIPT

12. Xanthoangelol E (65)

Anti-platelet

m.p. 237-238°C,

15.1-

activity by COX-1

234-235°C, 261-

85.5

inhibition

262°C

Anti-platelet

Yellow needles,

activity by

TXB2

m.p. 185-187°C,

and

λmax 221 nm

HTA

NU

Thromboxane B2,

72

PT

chalcones (53-55)

234 nm

RI

11. Thiophene based

aggregation

SC

(52)

(5),

heptadecatrienoic

ETA

acid (HTA), 12-

(50)

MA

12-hydroxy-5,8,10-

74, 103

TE

D

hydroxy-5,8,10,14eicosatetraenoic

AC CE P

acid (ETA) inhibition

13. Hydroxysafflor yellow A (HSYA) (66)

14. Lonchocarpin (LCC) (67) 15. Derricin (DRC) (68)

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Anti-platelet

Yellow powder,

WRP

activity by

m.p. 184-186°C

(0.99)

inhibiting WRP

and

and PMN

PMN

aggregation

(0.7)

inhibition of PDE,

Yellow crystals,

or elevation of

m.p. 109°C

cAMP and cGMP

Insoluble in

levels or inhibition

water, Log P

75, 104

NA

76, 107

NA

76, 105

ACCEPTED MANUSCRIPT of TX formation

6.38, b.p. 503.5°C

Anti-platelet,

m.p. 336-337°C

cardioprotective

chalcone (YLSC) (69)

action

SC

chalcones (72-74)

Anti-platelet

m.p. 270-271°C,

activity by

MA

1

40-42

253°C

Cholesteryl Ester

Yellow solid,

CETP

Transfer Protein

m.p. 148-151°C,

(88),

(CETP) inhibitor,

poorly soluble in

DGAT

Diacylglycerol

water, λmax 279

(50.3)

λmax 205

194

41, 105

NA

3-37.6

21, 43

AC CE P

TE

D

(75)

78

211-212°C, 252-

inhibition of COX-

18. Xanthohumol (XN)

50

NU

17. Hydroxylated

77, 101

RI

hydroxyl-benzofuran

NA

PT

16. 17-methoxyl-7-

Acyltransferase (DGAT) inhibitor, inhibitors of triglyceride (TG) synthesis

19. Xanthohumol B (76)

Diacylglycerol Acyltransferase (DGAT) inhibitor

20. Hydroxylated chalcones and their

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Pancreatic Lipase (PL) inhibitors

ACCEPTED MANUSCRIPT glycosidic hybrids (7783) m.p. 127-129°C,

NA

22, 45

(LPL) activators

119-121°C, 137-

NA

93

NA

94, 104

NA

95, 107

NA

NA

102, 104

m.p. 86-88°C,

NA

102, 103

RI

fibrates (84-87)

Lipoprotein Lipase

PT

21. Substituted chalcone

SC

139°C, 260262°C

170-172°C, 186188°C

improves serum

b.p. 542°C,

HDL levels and

practically

TE

HD) (93)

MA

23. 4-hydroxyderricin (4-

(LPL) activators

D

(90-92)

m.p. 176-178°C,

NU

22. Lupeol-based chalcones Lipoprotein Lipase

reduces liver

insoluble in

AC CE P

triglyceride content water, Log P

24. Xanthoangelol (94)

4.44

decrease serum

Yellow needle,

LDL levels and

m.p. 114-115°C

total cholesterol content

25. 3,2',4',6'-tetrahydroxy-

treatment of

4,3'-dimethoxy

ischemia

chalcone (98)

reperfusion

26. 2-hydroxychalcone (99) injuries, vascular injury response,

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soluble in

ACCEPTED MANUSCRIPT methanol, σ

regression, and

1.191

prevention of

Yellowish-white

coronary

crystals, m.p.

atherosclerosis

124°C

102, 105

NA

102, 103

NA

102, 103

NA

102, 106

mixed receptor

Yellow columnar NA

102, 107

blockade activity

crystal, m.p. 140-

(α- and β-

142°C

adrenergic

Yellow needle,

receptors)

m.p. 101°C

inhibits

Amorphous

coagulation factor

yellow powder,

Xa

m.p. 122-124°C,

β-adrenergic

methoxychalcone (101)

Yellow needle,

receptor blockade

λmax 349

action

MA

29. Licochalcone B (102)

AC CE P

TE

D

30. Isoliquiritigenin (103)

31. Glypallichalcone (104)

32. Licochalcone A (105)

33. Licochalcone G (106)

m.p. 199-200°C,

NU

28. 2',4'-dihydroxy-6'-

RI

PT

NA

SC

27. Neobavachalcone (100)

vascular lesion

Yellow needle, m.p. 195-197°C Orange yellow fine powder, m.p. 191-194°C

NA

102, 105

NA

102, 103

λmax 258 nm m.p. Melting Point; b.p. Boiling Point; σ Density; [α]D Specific rotation; NA not available 77 | P a g e

ACCEPTED MANUSCRIPT

AC CE P

TE

D

MA

NU

SC

RI

PT

GRAPHICAL ABSTRACT

In this review, a comprehensive study of chalcones modulating various cardiovascular, hematological, anti-obesity targets, and their SARs, and MOAs have been described.

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Therapeutic potential of chalcones as cardiovascular agents.

Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people ...
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