Synthesis, reactions, and applications of chalcones: A review European Journal of Chemistry 13 (2) (2022) 241-252 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.13.2.241-252.2245 European Journal of Chemistry View Journal Online View Article Online Synthesis, reactions, and applications of chalcones: A review Nesrin Mahmoud Morsy * and Ashraf Sayed Hassan Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Dokki 12622, Egypt * Corresponding author at: Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Dokki 12622, Egypt. e-mail: nesrinmorsy@yahoo.com (N.M. Morsy). 10.5155/eurjchem.13.2.241-252.2245 Received: 07 March 2022 Received in revised form: 19 April 2022 Accepted: 26 April 2022 Published online: 30 June 2022 Printed: 30 June 2022 Considering the essential biological and medicinal properties of chalcones, the synthesis of these compounds has attracted the interest of medicinal and organic chemists. This review aims to describe the different strategies developed so far for the synthesis of chalcones and their applications. After a brief introduction of the chalcones and their biological activities, different synthetic approaches such as chemical and other methods are described and organized on the basis of the catalysts and the other reagents employed in the syntheses. Some of the reactions have been applied successfully to the synthesis of biologically important compounds. Moreover, the biological and pharmacological activities of chalcones have been shown. Synthesis Reactions Chalcones Applications Chemical method Biological activity Cite this: Eur. J. Chem. 2022, 13(2), 241-252 Journal website: www.eurjchem.com 1. Introduction Chalcone the name was coined by the two authors, Stanislaw Kostanecki and Joseph Tambor [1]. Chalcones (aromatic ketones and enones, α,β-unsaturated ketone) consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system [-CO-CH=CH-] [2]. It has the general structural formula as shown in Figure 1. Chalcone may be called some names as benzylideneacetophenone, phenyl styryl ketone, benzalacetophenone, α-phenyl-β-benzoylethylene, and others [3,4]. 1 2 3 1'' 2'' 3'' 4'' 5'' 6'' O 1'2' 3' 4' 5' 6' Figure 1. General structural formula of chalcone. Many of chalcones possess interesting pharmacological properties such as antibacterial [5], antifungal [6], antiviral [7], anti-HIV activity [8], 5-lipoxygenase inhibitor [9], anticancer [10-12], cytotoxic activity [13], antimalarial [14], antiulcer [15], antileishmanial [16], and anti-inflammatory [17]. Recently, several chalcone-based compounds have been approved for clinical use, for example Metochalcone I was once marketed as a choleretic drug, while Sofalcone II was previously used as an antiulcer and nucoprotective drug (Figure 2) [18]. In addition, chalcones and their derivatives have great applications as sweeteners [19,20], fluorescent whitening factor [21], heat maintenance [22], and brightening agent [23]. O OO O O OH O O OO Metochalcone I Sofalcone II Figure 2. Structures of approved chalcone-based drugs. Based on the above arguments, in continuation of our program [24-61], and related work [62-67], therefore, this review aims to highlight and summarize the synthetic methodologies, reactions, applications, and biological activities of chalcones. 2. Synthetic methodology of chalcones 2.1. Claisen-Schmidt condensation ABSTRACT REVIEW ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.2.241-252.2245 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.2.241-252.2245 mailto:nesrinmorsy@yahoo.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.2.241-252.2245&domain=pdf&date_stamp=2022-06-30 242 Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 O O OH H2O OHC 1 2 3 + Scheme 1 Scheme 2 + 9 8 OH O2N O 7 CHO OH NO2 O OCH3 HCl OCH3 Scheme 3 CHO 2 + O P C2H5O C2H5O O - O 10 3 Scheme 4 Microwave irradiation EtOH / NaOH + O 13 O OCH3 CHO Cl Cl 11 12 H3CO Cl Cl Scheme 5 2.1.1. Synthesis of monochalcone This method was used for the preparation of chalcone 3 (with a yield of approximately 85%) by adding an equimolar amount of acetophenone 1 to benzaldehyde 2 in the presence of aqueous alcoholic alkali (10 to 60% alkali) at 50 ° C for 12-15 hours or one week at room temperature (Scheme 1) [68]. 2.1.2. Synthesis of bis-chalcone Di-ketone (4), 1,1'-(2,4,6-trimethoxy-1,3-phenylene)diet- hanone, was reacted with aldehyde 5a-g in the methanol as a solvent in the presence of 50% potassium hydroxide to give bis- chalcones 6a-g (Scheme 2) [69]. 2.2. Using hydrochloric acid 2-Hydroxy-5-nitro-acetophenone (7) was reacted with 4- methoxybenzaldehyde (8) to give 1-(2-hydroxy-5-nitrophen- yl)-3-(4-methoxyphenyl)prop-2-en-1-one (9) via using hydro- chloric acid (Scheme 3) [70]. 2.3. Chalcone synthesis from phosphonate carbanion Chalcone 3 was obtained by the reaction of benzaldehyde (2) with phosphonate carbanion (10) which was produced from diethyl phenacyl phosphonate (Scheme 4) [71-74]. 2.4. Using microwave conditions Chalcone 13 was prepared by adding of p-methoxyaceto- phenone (11) to 2,4-dichlorobenzaldehyde (12) in the presence of sodium hydroxide (1-2 pellets) in absolute ethanol under microwave irradiation conditions (a microwave oven for 50 seconds) (Scheme 5) [75]. Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 243 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 Sonochemical conditions Zeolite + O 15 O CHO R 1 14 R Scheme 6 Enzyme Imidazole n-Octane + R O 17 O R CHO 16 2 O R + E-isomer Z-isomer 18 Scheme 7 Scheme 8 2.5. Using solvent-free conditions Sonochemical conditions were used in the synthesis of chalcones 15 from acetophenone (1) with aldehyde derivatives 14 in the presence of zeolite as a catalyst (the catalyst was prepared by grafting amino groups on sodium and cesium exchanged X zeolite, a new type of amino grafted zeolite) under solvent-free conditions (Scheme 6) [76]. 2.6. Using the biocatalysts Lipases are industrial biocatalysts, which are involved in several novel reactions occurring in both aqueous and non- aqueous mediums. The reaction of aliphatic ketone 16 and benzaldehyde (2) was catalyzed by using recombinant D- amino-acylase (EC 3.5.1.81) and imidazole in the presence of n- octane as a solvent for the formation of the E-isomer of alkyl- but-3-en-2-ones (17) and the Z-isomer of alkyl-but-3-en-2-ones (18) with yields of 74 and 26%, respectively (Scheme 7) [77]. 3. Reactions of chalcones 3.1. Reaction with phenylhydrazine Chalcones 19 were reacted with phenylhydrazine (20) in the presence of a mixture of acetic acid-sodium acetate aqueous solution at room temperature. The optimum reaction condition was the molar ratio of chalcone: phenylhydrazine: sodium acetate was 1:3:0.15 for the formation of 1,3,5-triaryl-2- pyrazolines 21 in 83–96% yield (Scheme 8) [78]. 3.2. Reactions with hydrazine hydrate 3.2.1. Bis-chalcones with hydrazine hydrate Bis-chalcones (22) were reacted with hydrazine hydrate in the presence of acetic acid to give bis-3,5-diphenyl pyrazoline (23) (Scheme 9) [79]. 3.2.2. Chalcones with hydrazine hydrate using ultrasound irradiation conditions The cyclo-condensation of 1,5-substituted diphenyl-1,4- pentadien-3-ones 24 with hydrazine hydrate in a cyclizing agent such as acetic acid in ethanol under the ultrasound irradiation method. The reaction mixture was sonochemically irradiated for 10 to 25 minutes to give N1-acetyl-5-aryl-3- (substituted styryl)pyrazolines 25 (Scheme 10) [80]. 3.2.3. Chalcones with hydrazine hydrate using microwave irradiation Chalcone 13 reacted with hydrazine hydrate in glacial acetic acid and absolute ethanol under microwave conditions. The reaction mixture was placed in a microwave oven for 160 seconds for the formation of 1-(5-(2,4-dichlorophenyl)-3-(4- methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone 26 (Scheme 11) [75]. 244 Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 Scheme 9 Scheme 10 Scheme 11 R O OCH3 NH2OH HCl R OCH3 N O R= H, Br, F, CH3, OCH3 27 28 Scheme 12 3.3. Reaction of chalcones with hydroxylamine 3.3.1. Synthesis of methoxynaphthaline isoxazole derivatives When 1-(4’-substituted-phenyl)-3-(6‘’-methoxynaphthaline) -2-propene-1-one 27 were reacted with hydroxylamine, the isoxazole derivative 28 were formed (Scheme 12) [81]. 3.3.2. Synthesis of benzofuryl isoxazole derivatives Benzofuryl chalcone derivatives 29 were condensed with hydroxylamine hydrochloride in ethanol as a solvent in the presence of sodium hydroxide to form isoxazole derivatives 30 (Scheme 13) [82]. 3.4. Reactions of chalcones with urea and thiourea 3.4.1. Synthesis of pyrimidine and theinopyrimidine derivatives Some chalcones 31 were reacted with urea in acidic medium to give the derivative pyrimidine-2-one 32, while it can give the derivatives pyrimidine-2-thione 33 when reacted with thiourea in basic media (Scheme 14) [83]. 3.4.2. Reaction with thiourea using microwave irradiation Pyrimidine-2-thione derivatives 35a-j were produced from the condensation of chalcone 34a-j with thiourea dissolved in ethanol and in the presence of diluted HCl. These reactions were carried out using the microwave technique. The reaction mixture was placed in a microwave oven for 55-60 seconds (Scheme 15) [75]. Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 245 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 O R O NH2OH.HCl EtOH, NaOH O N O R O N Cl Br R = 29 30 Scheme 13 H2N O NH2 HCl NHN O R1 R R O R1 H2N S NH2 NaOH NHN S R1 R N HS O S HN OO R = R1= p-nitrophenyl, p-chlorophenyl, 3-indolyl. and p-N-dimethylaminophenyl 31 32 33 Scheme 14 Scheme 15 O OCH3 OCH3 OH O Ar + NC NH2 X EtOH / Pip. Reflux O OCH3 OCH3 OH N Ar CN XH Ar = 5-methyl-2-furyl X = O, S36 37 Scheme 16 3.5. Reaction with 2-cyanoacetamide or 2-cyanothio acetamide Chalcone 36 and 2-cyanoacetamide or 2-cyanothio acetamide were reacted together in ethanol in the presence of piperidine to give 6-(6-hydroxy-4,7-dimethoxybenzofuran-5- yl)-4-(5-methylfuran-2-yl)-3-cyanopyridine derivatives 37 (Scheme 16) [84]. 3.6. Reaction with 1-methyl-6-oxo-4-aryl-pyrimidine-5- carbonitrile Chalcones 38a-h were reacted with 2-hydrazino-1-methyl- 6-oxo-4-phenylpyrimidine-5-carbonitrile (39a) and 2-hydra- zino-1-methyl-6-oxo-4-(4-chlorophenyl)-pyrimidine-5-carbo- nitrile (39b) [85] in absolute ethanol and in the presence of sodium hydroxide. 246 Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 Scheme 17 Scheme 18 Scheme 19 The reaction was then heated under reflux conditions for 72 hours to give 2-(substituted)-1-methyl-6-oxo-4-aryl-pyrimi- dine-5-carbonitrile derivatives 40a-h and 41a-h, respectively, (Scheme 17) [86]. 3.7. Reaction with 1,2-diaminebenzene Chalcone derivatives 42 were reacted with o-pheny- lenediamine to give 2,4-disubstituted-1,5-benzodiazepine 43 (Scheme 18) [87]. 3.8. Reaction with 2-aminothiophenol Benzothiazepine derivatives 45a-v were prepared from the reaction of chalcones 44a-v with 2-aminothiophenol in toluene and in the presence of TFA (Scheme 19) [88-92]. 3.9. Reactions with thiosemicarbazide and isonicotinic acid Chalcones 46 were dissolved in absolute ethanol in the presence of sodium hydroxide and added to thiosemicarbazide, then glacial acetic acid was added and the mixture was refluxed for 7 hours to give 4,5-dihydro-pyrazole-1-carbothioamide derivatives 47. Furthermore, chalcones 46 were added to a mixture of isonicotinic acid and glacial acetic acid in ethanol, and then the reaction was refluxed for 5 hours to give (4,5- dihydro-pyrazol-1-yl)(pyridin-4-yl)methanone 48 (Scheme 20) [93]. 4. Biological applications of chalcones 4.1. Chalcones as antimicrobial agents Nitrofuryl chalcone 49, 1-(2-fluorophenyl)-3-(5-nitro furan-2-yl)prop-2-en-1-one, was tested for its antibacterial activity and explored that this compound exhibited activity against Staphylococcus Landon (Figure 3) [94]. Chalcones which are bearing indole moiety 50 gave antibacterial activity against Escherichia coli and Bacillus cereus. In addition, chalcones 50 gave antifungal activities against Fusarium oxysporium and Macrophomina phaeolina (Figure 4) [95]. Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 247 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 OO2N O F 49 Figure 3. Nitrofuryl chalcone 49 as antibacterial agent. O R H N R= OCH3, NO2, Cl, Br 50 Figure 4. Chalcones containing the indole moiety 50 exhibited antimicrobial activity. N N N MeO MeO O N N N MeO MeO O Cl N N N MeO MeO O NO2 N N N MeO MeO O O O N N N MeO MeO O OMe N N N MeO MeO O OMe OMe MeO 53 55 51 52 54 56 Figure 5. Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcones 51-56 showed anticancer activities. H3CO HO O X N O NH.NH2 H2NHN S NH2 HO H3CO NN S H2N X HO H3CO N N O X N X= H, OCH3, Cl, Br, NO2 46 47 48 Scheme 20 4.2. Chalcones as anticancer The new derivatives of tetrahydro- [1,2,4] triazolo [3,4-a] isoquinoline chalcones 51-56 showed anticancer activities against breast cancer cell lines (MCF-7) especially compounds 53 and 56 that offered the lowest IC50 values (50.05, and 27.15 μg/ml) respectively, relative to the positive control 5- fluorouracil (5-FU) (IC50 = 178 μg/ml) (Figure 5) [96]. 248 Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 H3CO H3CO H3CO O OCH3 OH57 Figure 6. α-Methyl chalcone 57 showed cytotoxic activity against the K562 human leukaemia cell. O O R1 R O Ar Ar= Heteroaryl R= -OH, -OR', where R' = alkyl R1= -H, -alkyl 58 Figure 7. The chalcones-pyran moiety 58 showed biological activities. O N NHN R3 R4 R1 R2 R1, R2, R3= H, alkyl, alkoxy, halo R4= H, alkyl, or aryl 59 Figure 8. Chalcone 59 showed considerable activities against human immunodeficiency virus (HIV). HO OCH3 OH OH O 60 Figure 9. Hydroxy chalcones 60 showed antioxidant properties. N H O N H O OCH3 OCH3 OCH3 61 Figure 10. Phenylurenyl chalcone 61 showed antimalarial activity. A series of substituted chalcones was synthesized and screened for cytotoxic activity against the K562 human leukaemia cell line. α-Methyl chalcone, 3-(3-hydroxy-4- methoxyphenyl)-2-methyl-1-(3, 4, 5-trimethoxy-phenyl)prop- 2-en-1-one (57), was found to be the most active [IC50 (K562) 0.21 nM] (Figure 6) [97]. Chalcones with pyran moiety 58 were reported as anti- breast cancer, osteoporosis, and menopausal disorders (Figure 7) [98]. 4.3. Chalcones as antiviral Chalcones with the substituted triazole moiety and having fluoro substitution 59 showed considerable activity against human immunodeficiency virus (HIV) (Figure 8) [98]. 4.4. Chalcones as antioxidants Hydroxychalcone 60 was examined for its ability to inhibit in vitro oxidation of human low-density lipoprotein (LDL). At concentrations of 5 and 25 μM, hydroxy chalcone 60 tested inhibited the oxidation of LDL (50 μg protein/ml) induced by 2 μM copper sulfate. Hydroxy chalcone 60 showed antioxidant properties (Figure 9) [99]. 4.5. Chalcones as antimalarial Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of the in vitro development of a chloroquine resistant strain of Plasmodium falciparum, the activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, β-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1- phenyl-3-(4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)urea (61) with an IC50 of 1.76 μM for inhibition of P. falciparum development (Figure 10) [100]. Chalcone-acridine derivatives 62a-e have been character- rized and screened for in vitro antimalarial activity against Plasmodium falciparum NF-54. All chalcones showed complete inhibition at a concentration of 10 μg/mL (Figure 11) [101]. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/antimalarial-activity https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/plasmodium-falciparum Morsy and Hassan / European Journal of Chemistry 13 (2) (2022) 241-252 249 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.241-252.2245 N HN O R R= H, 3-CH3, 4-CH3, 3,4,5-tri-OCH3, 4-Cl 62a-e Figure 11. Chalcone-acridine derivatives 62a-e showed antimalarial activity. H3CO O OH 64 O OCH3 H3CO OCH3 63 F Figure 12. The two chalcones 63 and 64 possess anti-tubercular activity. Figure 13. Chalcones 65 possess anti-diabetic activity. 4.6. Chalcones as anti-tubercular Chalcone 63 having antimycobacterial activity. Further- more, a new fluorine-substituted chalcone analog 64 was synthesized and its antitubercular efficacy was evaluated against the strain of Mycobacterium tuberculosis H37Rv (Figure 12) [102]. 4.7. Chalcones as anti-diabetic Chalcones 65 were synthesized and evaluated for their anti- diabetic activity through an oral glucose tolerance test to gain preliminary information regarding the antihyperglycemic effect in normal Swiss albino male mice. The derivatives showed a significant blood glucose lowering effect. The compounds were selected for in vivo antidiabetic activity and found to be potential candidates for the treatment of diabetes (Figure 13) [103]. 5. Conclusions In this Review, a wide range of synthetic strategies of chalcones have been discussed. We started with chemical and other methods for the synthesis of chalcones, followed by their reactions with various reagents under different conditions, and finally, presenting their diverse biological and pharmacological activities such as antimicrobial, anticancer, antiviral, anti- diabetic, and antioxidant. In this report, we explain that chalcones are based on the construction of new heterocyclic compounds that are used in the medical field. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. CRediT authorship contribution statement Conceptualization: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Methodology: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Software: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Validation: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Formal Analysis: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Investigation: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Resources: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Data Curation: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Writing - Original Draft: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Writing - Review and Editing: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Visualization: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Funding acquisition: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Supervision: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan; Project Administration: Nesrin Mahmoud Morsy, Ashraf Sayed Hassan. ORCID and Email Nesrin Mahmoud Morsy nesrinmorsy@yahoo.com https://orcid.org/0000-0003-3636-1767 Ashraf Sayed Hassan ashraf_salmoon@yahoo.com https://orcid.org/0000-0002-4771-716X References [1]. Kostanecki, S.; Tambor, J. Ueber die sechs isomeren Monooxy benzalacetophenone (Monooxychalkone). Ber. Dtsch. Chem. Ges. 1899, 32, 1921–1926. [2]. Rupe, H.; Wasserzug, D. Notizen über chromophore gruppirungen. Ber. Dtsch. Chem. Ges. 1901, 34, 3527–3531. [3]. Rammohan, A.; Reddy, J. S.; Sravya, G.; Rao, C. N.; Zyryanov, G. V. Chalcone synthesis, properties and medicinal applications: a review. Environ. Chem. Lett. 2020, 18, 433–458. [4]. Ahmad, M. R.; Khan, M. H. R.; Sastry, V. G.; Bano, N.; Anwar, S.; Prasad, Y. R. A comparative study on synthesis of some novel α,β-unsaturated carbonyl derivatives and their antioxidant potential. Eur. J. Chem. 2012, 3, 186–190. [5]. Nielsen, S. F.; Boesen, T.; Larsen, M.; Schønning, K.; Kromann, H. 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The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://eurekamag.com/research/013/960/%20013960550.php http://eurekamag.com/research/013/960/%20013960550.php http://www.pharmatutor.org/magazines/articles/%20december-2013/review-on-chalcones-importance http://www.pharmatutor.org/magazines/articles/%20december-2013/review-on-chalcones-importance http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Synthetic methodology of chalcones 2.1. Claisen-Schmidt condensation 2.1.1. Synthesis of monochalcone 2.1.2. Synthesis of bis-chalcone 2.2. Using hydrochloric acid 2.3. Chalcone synthesis from phosphonate carbanion 2.4. Using microwave conditions 2.5. Using solvent-free conditions 2.6. Using the biocatalysts 3. Reactions of chalcones 3.1. Reaction with phenylhydrazine 3.2. Reactions with hydrazine hydrate 3.2.1. Bis-chalcones with hydrazine hydrate 3.2.2. Chalcones with hydrazine hydrate using ultrasound irradiation conditions 3.2.3. Chalcones with hydrazine hydrate using microwave irradiation 3.3. Reaction of chalcones with hydroxylamine 3.3.1. Synthesis of methoxynaphthaline isoxazole derivatives 3.3.2. Synthesis of benzofuryl isoxazole derivatives 3.4. Reactions of chalcones with urea and thiourea 3.4.1. Synthesis of pyrimidine and theinopyrimidine derivatives 3.4.2. Reaction with thiourea using microwave irradiation 3.5. Reaction with 2-cyanoacetamide or 2-cyanothio acetamide 3.6. Reaction with 1-methyl-6-oxo-4-aryl-pyrimidine-5-carbonitrile 3.7. Reaction with 1,2-diaminebenzene 3.8. Reaction with 2-aminothiophenol 3.9. Reactions with thiosemicarbazide and isonicotinic acid 4. Biological applications of chalcones 4.1. Chalcones as antimicrobial agents 4.2. Chalcones as anticancer 4.3. Chalcones as antiviral 4.4. Chalcones as antioxidants 4.5. Chalcones as antimalarial 4.6. Chalcones as anti-tubercular 4.7. Chalcones as anti-diabetic 5. Conclusions Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField110: PrintField111: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: PrintField210: PrintField211: