Research Article

Chemical and Biological Potentials of Chalcones: A Review

1*, D Vidya Sagar² and Afzal Basha Shaik³

¹Department of Pharmacy, Victoria College of Pharmacy, India

²Department of Pharmacy, Veerayatan Institute of Pharmacy, India

³Department of Pharmacy, Vignan Pharmacy College, India

Submission: November 27, 2015; Published: December 31, 2015

*Corresponding author: NShaik Khadar Yazdan, Department of Pharmacy, Victoria College of Pharmacy, Nallapadu, Guntur, Andhra Pradesh, India; Email: bashafoye@gmail.com

How to cite this article: Shaik Khadar Y, Vidya S D, Afzal B S. Chemical and Biological Potentials of Chalcones: A Review. Organic & Medicinal Chem IJ. 2015; 1(1): 555553. DOI: 10.19080/OMCIJ.2015.01.555553

Abstract

Plants from the natural world are linked with the treatment of different human ailments. This is due to the presence of different classes of chemical constituents. Flavonoids are one such class of natural constituents responsible for the activity of plants. Chalcones are a class of natural open chain flavonoids that are linked by a three carbon spacer between two aromatic rings. Chalcones and their heterocyclic analogues enjoy a range of biological activities such as antimicrobial, antioxidant, cytotoxic, anticancer, antiprotozoal, antihistaminic, antiulcer and anti-inflammatory activities which makes these compounds as a special attraction for investigation. Additionally the bielectrophilic, ketovinyl chain between the two rings is highly reactive and acts as an important chemical synthon for constructing different five, six and seven membered heterocyclic scaffolds containing different hetero atoms like nitrogen, oxygen and sulfur atoms by abridgment with a variety of binucleophilic reagents. This review highlights on the chemical and biological potentials of chalcones.

Keywords:

Flavonoids; Chalcone; Biological Activities; Chemical Synthon; Bielectrophilic and Binucleophilic.

Introduction

Chalcone (Figure 1) is a generic term given to compounds bearing the 1, 3-diphenyl-2-propen-1-one framework and belong to the flavonoid family [1-3]. Chemically they are open-chain flavonoids in which the two aromatic rings are joined by a three carbonα,β-unsaturated carbonyl system. Chalcones are abundantly present in nature starting from ferns to higher plants4 and a number of them are polyhydroxylated in the aryl rings. In plants, chalcones are converted to the corresponding (2S)-flavanones in a stereospecific reaction catalyzed by the enzyme chalcone isomerase. This close structural and biogenetic relationship between chalcones and flavanones explains why they often co-occur as natural products.

All the chalcones give pink coloration with concentrated sulphuric acid (positive Wilson test)5 and when a phenolic hydroxyl group is present, they give violet coloration with alcoholic ferric chloride solution. Chalcones on heating with traces of iodine in dimethylsulphoxide (DMSO) for two hours give the corresponding flavones. Chalcones were converted into the corresponding flavonols by their oxidation using hydrogen peroxide in methanolic sodium hydroxide solution and these flavonols showed a characteristic greenish yellow fluorescence in ethanolic solution as well as with concentrated sulphuric acid.

General Methods of Synthesis Of Chalcones

Chalcones can be obtained by the acid or base catalyzed aldol condensation of acetophenones with aromatic aldehydes6-8.

2’-hydroxyacetophenone react with benzaldehyde in the presence of 0.1M NaOH to give the chalcone9 (Scheme 1).

NaOHLiquid phase Claisen–Schmidt condensation between 2’-hydroxyacetophenone and benzaldehyde was carried out over a zinc oxide supported metal oxide catalyst under solvent free conditions to form 2’-hydroxychalcone10 (Scheme 2).

2’,4’,5’-trimethoxyacetophenone, when condensed with equimolar proportions of aromatic aldehydes in the presence of 30 % alcoholic alkali at room temperature yield chalcones11 (Scheme 3).

Claisen-Schmidt condensation between benzaldehyde and acetophenone by sonochemical and thermally activated reactions over zeolite as catalyst under solvent free conditions give chalcone12 (Scheme 4).

4-acetyl-3-aryl-syndones when subjected to grinding with various aryl aldehydes in the presence of a base catalyst under solvent free conditions yield sydnone chalcones13 (Scheme 5).

Condensation of 2-naphthylmethyl ketones with substituted aryl aldehydes in the presence of NaOH under methanol as solvent gave the corresponding chalcones14 (Scheme 6).

Molecular Spectral Studies of Chalcones

Molecular Spectral Studies of Chalcones

The major absorption band in chalcones (Band I) usually occurs in the range 340-390 nm, although chalcones lacking B-ring oxygenation may have their Band I absorption at considerably shorter wavelengths and Band II is usually a minor peak in the 220-270 nm region15. In the spectra of chalcones containing a free 4’’-hydroxyl group, the addition of NaOMe causes a 60-100 nm bathochromic shift of Band I with an increase in peak intensity. Chalcones without a 4’’-hydroxyl group but with either a free 2’’ or 4’- hydroxyl group also give, in the presence of NaOMe, a 60-100 nm bathochromic shift of Band I but without an increase in peak intensity16, 17. UV spectroscopy proved useful to distinguish between substituted chalcones and flavanones, which is not possible by EI mass spectrometry due to thermal isomerization of 2’-hydroxychalcones in the ion source18, 19.

Infra Red Spectroscopy

The α, β-unsaturated carbonyl group, characteristic of a chalcone usually appear as a prominent band in between 1625-1650 cm-1 in its IR spectrum20,21. The region at which other absorption bands appear depends on the type of aromatic / heteroaromatic rings as well as the substituents present on these rings.

Nmr Spectroscopy

The H-α and H-β protons of chalcones occur as two doublets (J= 17 Hz) in the ranges 6.7 – 7.4 ppm (H- α) and 7.3 -7.7 ppm (H- β) in the 1H NMR spectra22. The other aromatic protons usually appear in between δ 6.9-8.0, depending on the type of aromatic/ heteroaromatic ring and also based on the electronic effects of the substituents present on these rings. The large J value (17 Hz) clearly reveals the trans geometry for the chalcones. The carbonyl carbon of the chalcones usually appears between δ 188.6 and 194.6 in its 13C NMR spectrum23. The α and β- carbon atoms with respect to the carbonyl group give rise to characteristic signals in between δ 116.1-128.1 and δ 136.9-145.4 respectively, which can also be readily identified by their characteristic appearance as a six line multiplet in the half resonance decoupled spectrum24. The presence of 2’-hydroxy group shifts the carbonyl carbon shift downfield by 3 ppm relative to corresponding acetoxy and methoxy compounds, presumably owing to hydrogen bonding. The β-hydroxy chalcones are a relatively small group of chalcones that occur naturally sometimes as the enol- tautomers of dibenzoylmethane derivatives. The extent of keto-enol tautomerism is largely solvent dependent, and nuclear magnetic resonance spectroscopy (NMR) provides one of the best methods to determine the ratio of the tautomers present. In the 1H NMR spectra recorded in CDCl3, the exchangeable proton of the β-OH of the enol tautomer appears as a 1H singlet at δ 16.0, whereas the α-CH2 protons of the keto tautomer appear as a 2H singlet at δ 4.50. Another diagnostic resonance is the 1H methine singlet of the enol tautomer (α-CH), which is found at δ 6.5, with its corresponding C- α resonance at δ 90 to 92 in the ¹³C NMR spectra^{25, 26.}

Mass Spectrometry

Cleavage of the heterocyclic C-ring via a retro Diels-Alder (RDA) mechanism represents an important fragmentation pathway in chalcones. RDA fission leads to two characteristic fragments, which provides useful information as to the number of hydroxyl, methoxyl and other substituents on each ring27 (Scheme 7). The same information was also obtained by a HPLCtandam mass spectrometer system equipped with a heated nebulizer- atmospheric pressure chemical ionization (APCI) interface²⁸.

Scheme 7. A typical fragmentation pattern of a 2’-Hydroxy chalcone.

Therapeutic Potential Of Chalcones

AChalcone is unique template that is associated with several biological activities (Figure 1.1) and is also well known for synthesizing various heterocyclic compounds²⁹. They are secondary metabolites of terrestrial plants, precursors for the biosynthesis of flavonoids. The introduction of a halogen into the benzenoid part of these α, β-unsaturated ketones enhances their biological activity³⁰.

The compounds with chalcone as backbone have been reported to possess varied biological and pharmacological activities31, including antimicrobial, anti-inflammatory, analgesic, cytotoxic, antitumor, antimalarial, antitubercular, antiviral, anti-HIV, antiulcerative, antileishmanial, antioxidant, antiprotozoal, antihistaminic, antifedent, immunomodulatory, anticonvulsant, antihyperglycemic, antihyperlipidemic and antiplatelet activities. Thus chalcones continue to attract considerable scientific attention because of their association with a variety of biological activities. Given below is a brief account of various modifications reported on chalcones, which resulted in a variety of biological and pharmacological activities.

Antimicrobial activity

The antimicrobial activity of chalcones is being increasingly documented. Many research groups either isolated or synthesized chalcones that possess antimicrobial activity. The presence of a reactive α, β-unsaturated keto function in chalcones was found to undergo conjugate addition with a nucleophilic group like a thiol group in an essential protein, thus partly contributing for their antimicrobial activity, which may be altered depending on the type and position of the substituents on the aromatic rings.

Prasad et al.32 synthesized 3-[1-oxo-3-(2, 4, 5-trimethoxyphenyl)-2-propenyl]-2H-1-benzopyran-2-ones (2) that showed significant antimicrobial activity against .subtilis, B.pumilis and E.coli> when tested at a concentration of 1000 μg/ ml. The study revealed the importance of electron releasing groups such as hydroxyl and methoxyl groups in enhancing the activity. Chalcones with halogen substituents like bromine and chlorine contributed favorably to the antifungal activity.

Nielsen et al.33 described the bioisosteric replacement of the essential 4’-hydroxy group in the hydroxychalcones with bioisosters of varied degrees of acidity which resulted in both more potent and more soluble compounds. Exchanging the hydroxyl group, particularly with a carboxy group resulted in a potent compound with a high aqueous solubility. Further optimization and SAR analysis resulted in soluble and potent carboxychalcones having dibromo or trifluoromethyl substitution on B-ring (3). The MIC values for these compounds were found to be 2 μM and 40 μM respectively when tested against the Gram-positive bacterium Staphylococcus aureus. A dibromo or trifluromethyl substitution on B-ring was found to enhance the lipophilic character, while the carboxy group on A-ring contributed to the required aqueous solubility.

Karthikeyan et al.34 synthesized 3-aryl-1-(2,4-dichloro- 5-fluorophenyl)-2-propen-1-ones (4) showing antimicrobial activity, again consistent with the observations that the halogens possess favorable lipophilic character required for antimicrobial activity.

Prasad et al.³⁵ synthesized a chalcone (5) having a naphthalene moiety on one side and an aryl moiety having substituents on the other side, which showed significant antifungal activity against A.niger and R.oryzae. This compound can also be considered to provide optimal hydrophilic and hydrophobic properties as evidenced by hydroxyl groups and the halogens.

Tsukiyama et al.36 isolated a retrochalcone, licochalcone-C (6) from Glycyrrhiza infanta which showed potent antibacterial activity.

Machodo et al.³⁷ isolated isoliquiritigenine (7) which showed antibacterial activity.

Rao et al.³⁸ synthesized chalcones having chlorine and fluorine substitution (8), which showed antimicrobial activity.

Nowakowska et al.³⁹ synthesized a series of substituted chalcones (9) and tested for their antibacterial and antifungal activities. The physico-chemical properties of these novel chalcones which contributed favourably to the observed activities were also determined.

Boeck et al.⁴⁰ synthesized novel xanthoxylin-derived chalcones (10) showing antifungal activity.

Sohly et al.⁴¹ isolated prenylated chalcones (11) from the leaves of Malclura tinctoria possessing antifungal activity.

Stevaz et al.⁴² isolated a 2’, 4’-dihydroxy-3’-methoxychalcone (12) from the methanolic extract of Zuccagnia punctata which exhibited antifungal activity.

Antimalarial activity

Dominguez et al.⁴³ synthesized chalcones (13) with sulfonamide moiety possessing antimalarial activity.

Dominguez et al.⁴⁴ synthesized phenylurenyl chalcones (14) that exhibited antimalarial activity.

Anti-HIV activity

Wu et al.⁴⁵ isolated a chalcone (15) that exhibited the anti- HIV activity with a good therapeutic index.

Xu et al.⁴⁶ isolated butein (16) possessing anti-HIV activity.

Nakagawa et al.⁴⁷ isolated a unique potent chalcone (17) from genus Desmos showing anti-HIV activity.

Antileishmanial activity

Hermoso et al⁴⁸ synthesized a dihydrochalcone (18) having antileishmanial activity.

Santos et al.⁴⁹ synthesized 2’,6’-dihydroxy-4’- methoxychalcone (19) that showed significant antileishmanial acitivity

Antitubercular activity

Kumar et al.⁵⁰ synthesized a chalcone (20) that exhibited antitubercular activity.

Kumar et al.⁵¹ synthesized a chalcones (21) possessing antimycobacterial activity.

Antitumor activity

Moderate cytotoxicity was reported for a methylenedioxychalcone (22) isolated from the stem bark of Millettia leucantha⁵²

Francesco et al.⁵³ synthesized furanochalcones (23) possessing anticancer activity.

Miyataka et al.⁵⁴ have successfully designed and synthesized some new fluorinated 3,4-dihydroxychalcones and evaluated their biological activities with respect to anti peroxidation activity. All the fluorinated chalcones tested showed 5-lipoxygenase inhibition on rat basophilic leukemia-1. However, the 6-Fluoro-3,4-dihyroxy-2’,4’-dimethoxychalcone (24) was the most effective compound in the in vitro assay using a human cancer cell line panel consisting of 39 systems.

Lawrence et al.⁵⁵ synthesized a methoxylated chalcone (25) possessing good cytotoxic activity

Sato et al.⁵⁶ synthesized a fluorinated chalcone (26) exhibiting anticancer activity

Cunha et al.⁵⁷ isolated the chalcone lonchocarpin (27) from the roots of Lonchocarpus sericeus which showed cytotoxic activity.

Rodrigo et al.⁵⁸ studied the relationship between the structural characteristics of synthetic chalcones and their antitumor activity. Treatment of Hep G2 cells for 24 h with synthetic 2’-hydroxychalcones (28) resulted apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated reactivity indexes and the adiabatic electron affinities suggest a structure-activity relationship between the chalcone structure and the apoptosis in HepG2 cells.

AAnti-inflammatory and Analgesic activities

Shen et al.⁵⁹ synthesized a 2’-hydroxy-3,4-dichlorochalcone (29) possessing anti-inflammatory and cancer chemopreventive activity.

SIto et al.^>60 isolated a reduced chalcone (30) having cyclooxygenase-2 inhibitory activity.

Zhao et al.⁶¹ isolated dihydroxanthohumol (31) from fruits of Mallotus philippinensis which showed anti-inflammatory activity.

Antioxidant activity

Kostova et al.⁶² synthesized 2’-hydroxychalcones (32) which showed antioxidant activity.

Miranda et al.⁶³ synthesized a prenylated chalcone (33) exhibiting antioxidant activity.

Miscellaneous activities

Satyanarayana et al.⁶⁴ synthesized a 4’-hydroxy-4- methoxychalcone (34) exhibiting antihyperglycemic activity.

Soliman et al.⁶⁵ synthesized a tetrahydroxychalcone (35) that showed potent tyrosine- kinase inhibitory activity.

Ko et al.⁶⁶ synthesized a chalcone (36) showing the inhibition of nitric oxide production in lipopolysaccharideactivated macrophages.

Barford et al.⁶⁷ isolated an oxygenated chalcone, lichochalcone A (37) from the roots of the Chinese liquorice, Glycyrrhizae uralensis, which showed immunosuppressive property.

Baell et al.⁶⁸ synthesized a chalcone (38) having potassium channel modulatory activity.

Chalcones As Synthon In Chemical Synthesis

Chalcones are resourceful precursor for the synthesis of heterocyclic compounds (Figure 2). Chalcones undergo cyclization reactions with different reagents to form diverse classes of heterocyclic compounds ranging from five membered to seven membered rings containing nitrogen, oxygen and sulfur heteroatoms. In the cyclization reactions the highly reactive bielectrophilic ketovinyl chain condenses with a variety of binucleophilic reagents to generate an assortment of heterocyclic systems such derivatives pyrazolines, phenylpyrazoline and isoxazole (5-membered heterocyclics),⁶⁹ derivatives aminopyrimidines and cyanopyridines (6-membered heterocyclics)⁷⁰ and derivatives of 1,5-benzodiazepines, 1,5-benzoxazepines, and 1,5-bezothiazepines (7-membered heterocyclics).⁷¹

Conflicts of interest

The authors have no conflicts of interest.

References

1. Brone B, Peeters PJ, Marrannes R, Mercken M, Nuydens R, et al. (2008) Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol Appl Pharmacol 231(2): 150-156.
2. Gijsen HJ, Berthelot D, Zaja M, Brone B, Geuens I, et al. (2010) Analogues of morphanthridine and the tear gas dibenz[b,f][1,4] oxazepine (CR) as extremely potent activators of the human transient receptor potential ankyrin 1 (TRPA1) channel. J Med Chem 53(19): 7011-7020.
3. Danneberg P, Weber KH (1983) Chemical structure and biological activity of the diazepines. Br J Clin Pharmacol 16 Suppl 2 231S-244S.
4. Smith AJ, Tett SE (2010) BMC Health Services Research 30(10): 321. Wieczorek J, Peczynska-Czoch W, Mordarski M, Kaczmarek L, Becalski A, et al. (1986) Antineoplastic activity of azacarbazoles. III. Synthesis and antitumor evaluation of selected 2-, 3- aza- and diazaanalogues of carbazole. Arch Immunol Ther Exp (Warsz) 34(3): 323-326.
5. Ulrich J, Sylvain R, Arnaud T, Jerome K, William L, et al. (2004) Org Biomol Chem 2: 1476.
6. Jasztold Howorko R, Tylińska B, Biaduń B, Gebarowski T, Gasiorowski K (2013) New pyridocarbazole derivatives. Synthesis and their in vitro anticancer activity. Acta Poloniae Pharmaceutica 70(5): 823-832.
7. Lescot E, Muzard G, Markovits J, Belleney J, Roques BP, Le Pecq JB (1986) Synthesis of 11H-pyridocarbazoles and derivatives. Comparison of their DNA binding and antitumor activity with those of 6H- and 7H-pyridocarbazoles. Med Chem 29(9): 1731-1737.
8. Nathwani SM, Butler S, Fayne D, McGovern NN, Sarkadi B, et al. Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells. Cancer Chemother Pharmacol 66(3): 585-596.
9. Greene LM, Fleeton M, Mulligan J, Gowda C, Sheahan BJ, et al. (2005) The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo. Oncol Rep 14(5): 1357-1363.
10. Banerji B, Pramanik SK, Sanphui P, Nikhar S, Biswas SC (2013) Synthesis and cytotoxicity studies of novel triazolo-benzoxazepine as new anticancer agents. Chem Biol Drug Des 82(4): 401-409.
11. Li R, Farmer PS, Wang J, Boyd RJ, Cameron TS, et al. (1995) Molecular geometries of dibenzothiazepinone and dibenzoxazepinone calcium antagonists. Drug Des Discov 12(4): 337-358.
12. Ndubaku CO, Heffron TP, Staben ST, Baumgardner M, Blaquiere N, et al. (2013) Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]- 1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem 56(11): 4597-4610.
13. Schmidt AW, Reddy KR, Knölker HJ (2012) Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem Rev 112(6): 3193-3328.
14. Ghazala y, Abdul H, Erum A, Muhammad U, Almas H, et al. (2013) Synthesis, Antibacterial, and Antifungal Activities of Novel Pyridazino Carbazoles. Journal of Chemistry.
15. Mowbray CE, Burt C, Corbau R, Gayton S, Hawes M, et al. (2009) Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate. Med Chem Lett 19(20): 5857-5860.
16. Cichero E, Fossa P (2012) Docking-based 3D-QSAR analyses of pyrazole derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors. J Mol Model 18(4): 1573-1582.
17. Han Q, Chang CH, Li R, Ru Y, Jadhav PK, Lam PY (1998) Cyclic HIV protease inhibitors: design and synthesis of orally bioavailable, pyrazole P2/P2’ cyclic ureas with improved potency. J Med Chem 41(12): 2019-2028.
18. Loh B, Vozzolo L, Mok BJ, Lee CC, Fitzmaurice RJ, Caddick S, Fassati A (2010) Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides. Chem Biol Drug Des 75(5): 461-474.
19. Ali MA, Ismail R, Choon TS, Yoon YK, Wei AC, et al. (2011) Synthesis and anti-HIV activity of novel 3-substituted phenyl-6,7-dimethoxy- 3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues. Acta Pol Pharm 68(3): 343-348.
20. Singh B, Vashishtha B, Kishore D (2010) Book Proceedings of International Conference on Pure and Applied Chemistry-2010 (ICPAC-2010). Springer.
21. Jhanwar A, Tyagi R, Vashistha B, Srivastava V, Singh B, et al. (2009) Application Of Japp-Klingemann Reaction In The Synthesis Of Azacarbazole Derivatives. Intl J Chem Sci 7(4): 2222-2226.
22. Tyagi R, Singh B, Kishore D (2012) Synthesis of novel precursors of Pfitzinger reaction: A facile one-pot strategy to the synthesis of quinoline carboxylic acid derivatives of pyrazolo-carbazoles and azacarbazoles. J Chem Sci 124(2): 431-435.
23. Anand A, Kaur N, Kishore D (2014) An Efficient One Pot Protocol to the Annulation of Face “d” of Benzazepinone Ring with Pyrazole, Isoxazole, and Pyrimidine Nucleus through the Corresponding Oxoketene Dithioacetal Derivative. Advances in Chemistry.
24. Venkatapuram P, Boggu JMR, Akula B, Katta VR, Dandu BR (2000) Molecules, 5: 1281.
25. Bhawani S, Deepika M, Lalit BK, Talesara GL (2004) Indian J Chem Sect B 43B(6): 1306.
26. Chauhan SMS, Junjappa H (1976) Progress in Heterocyclic Chemistry. Tetrahedron 13(32): 1911.
27. Fukuii H, Inoguchi K, Nakano J (2002) Heterocycles 100(16): 257.
28. Archana R, Yamuna E, Rajendra Prasad KJ, Thiruvalluvar A, Butcher RJ (2010) Acta Crystallogr Sect E Struct Rep Online 66(9): 2299-2300.
29. Tyagi R, Kaur N, Singh B, Kishore D, Heterocyclic J (2014) Novel Synthetic Protocol for the Heteroannulation of Oxocarbazole andOxoazacarbazole Derivatives through Corresponding Oxoketene Dithioacetals. Chem 51(18).
30. Clarke HT, Read RR (1941) A Publication of Reliable Methods for the Preparation of Organic Compounds. Org Synth.1: 514.
31. P. Kumar, N. Chandak, P. Kaushik, C. Sharma, D. Kaushik, K. R. Aneja, P. K. Sharma (2012) Synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory–antibacterial agents. Med Chem Res 21(11): 3396-3405.