Comprehensive Review of Medicinally Privileged Chalcone: Advanced Synthetic Methods and Diverse Biological Activity

Chalcones belong to the flavonoid family and are a class of secondary metabolites that are present in both edible and medicinal plants [1]. Known as 1,3-diphenyl-2-propen-1-ones, these molecules have a delocalized π-electron structure and two aromatic rings connected by an α,β-unsaturated carbonyl group. Usually yellow to orange in hue, chalcones are polyphenolic compounds that help some plants' blooms become pigmented. They have attracted a lot of attention because of their possible health advantages and are found naturally in a variety of foods, including fruits, spices, teas, and soy-based products. Chalcones are present in nature as pheromones, plant allelochemicals, and insect hormones in addition to being present in food [2].In the biosynthesis of flavonoids, isoflavonoids, and aurones, chalcones also act as intermediates. Natural and synthesized chalcones have been the subject of much medicinal chemistry study in recent decades because of their diverse range of pharmacological actions, which include immunomodulatory, antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer properties. This review highlights the possible uses of chalcone derivatives in medicine by going over their chemical characteristics, therapeutic potential, and synthetic methods of production.[3]

2. Chalcone

1,3-diphenyl-2E-propene-1-one, another name for chalcone, is a substance that acts as an intermediary in the biosynthesis of flavones and aurones.[4] A benzylideneacetophenone scaffold with a three-carbon α, β-unsaturated carbonyl bridge connecting two aromatic rings is found in chalcones, which are naturally occurring precursors of flavonoids and isoflavonoids. As part of a group of naturally occurring chromophoric chemicals that were distinguished by their α, β-unsaturated carbonyl structure, Kostanecki and Tambor were the first to synthesis chalcones.[5] Chalcones are traditionally made via Claisen-Schmidt condensation, but more recent techniques including microwave-assisted irradiation have also been used. Chalcones have drawn more attention from researchers because of their straightforward structure, ease of synthesis, and numerous possible medicinal uses.[6] Chalcones have demonstrated diverse therapeutic effects, including anti-cancer, anti-inflammatory, anti-oxidant, anti-hypertensive, anti-diabetic, and anti-microbial activities, among others.[7]

3. Chalcones as various biological activities

3.1 Chalcones as Antioxidants

The body needs antioxidants because they shield cells from oxidative stress and free radical damage. Unstable chemicals known as free radicals have the ability to damage cells, causing aging and raising the risk of illnesses like cancer, heart disease, and neurological disorders. By giving free radicals electrons, antioxidants stabilize these molecules and stop additional cellular damage.[8] This procedure guards against the damaging effects of reactive oxygen species (ROS) and reduces oxidative stress. Chalcones exhibit potent antioxidant qualities because of their electron-rich phenolic structure.Among the many ways they work is by increasing the activity of important antioxidant enzymes including glutathione peroxidase, catalase, and superoxide dismutase.[9].Additionally, chalcones stimulate the Nrf2-ARE pathway, which increases the production of genes related to detoxification and antioxidant defense.[10] Furthermore, by blocking enzymes such as xanthine oxidase and NADPH oxidase, chalcones may lessen the generation of ROS. Additionally, their metal-chelating qualities help to minimize the development of ROS that are driven by metals.[11]

List of Antioxidants chalcones

3.2 Chalcones with Anticancer Properties

With over 10 million deaths per year, cancer continues to be one of the world's top causes of death. Over the next 20 years, it is anticipated that the incidence of cancer would increase by 47%, adding to the burden on the world's health.[12] Natural chalcones have showed promise in reducing the consequences of cancer, a potentially fatal disease that can be challenging to cure. They can enhance oxidative stress, decrease enzyme activity, cause apoptosis, and promote cell cycle arrest—all of which are factors in the demise of cancer cells.[13] Chalcones have also been shown to suppress inflammation, angiogenesis, and multidrug-resistant proteins, particularly in gastrointestinal malignancies. Chalcones' potential for treating breast, liver, and lung cancers is explicitly examined in this review.[14]

List of Anticancer chalcones

3.3 Chalcones as Antidiabetic Agents

By stimulating peroxisome proliferator-activated receptor gamma (PPARγ), a crucial nuclear receptor involved in insulin action, chalcones have been demonstrated to increase insulin sensitivity[15].Chalcones also aid to lessen postprandial blood sugar rises by inhibiting the enzymes α-glucosidase and α-amylase, which break down carbohydrates[16]. Additionally, studies show that chalcones increase the absorption of glucose via activating the AMP-activated protein kinase (AMPK) pathway, which facilitates the translocation of glucose transporter 4 (GLUT4) to the cell membrane[17]. Chalcones also have antioxidant qualities that aid in reducing oxidative stress, which is a significant contributor to the emergence of issues associated with diabetes[18].

Two novel antidiabetic chalcones isolated from the plant Angelica keiskei

3.4 Anti?Inflammatory Chalcones

Chalcones are known to have strong anti-inflammatory properties. Important substances with potent anti-inflammatory properties include isoliquiritigenin from licorice, xanthohumol from hops (Humulus lupulus) and several tree barks, and flavokavain A from the kava plant[19].These chalcones function by blocking pro-inflammatory mediators such as prostaglandin E2 (PGE2), nitric oxide (NO), and cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)[20]. They also prevent the activation of important inflammatory pathways, including mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB). Chalcones help lower inflammation by focusing on these pathways, which may have therapeutic advantages for ailments like inflammatory bowel disease and arthritis[21].

3.5 Chalcones as Neuroprotective Agents

via inhibiting monoamine oxidase B (MAO-B) and causing neuroinflammatory effects via activating the Nrf2 pathway, chalcones have shown encouraging promise in Parkinson's disease[22]. Furthermore, by blocking A1 and A2A receptors and inducible nitric oxide synthase (iNOS), chalcones can affect other pathways that restrict immune responses and stop additional damage[23] .The breakdown of amines essential to the brain's emotional and cognitive processes is aided by MAO enzymes. Chalcones are effective, according to a review of MAO-B inhibitors, and changes to their molecular structure may increase their activity by affecting a number of physiological and chemical characteristics[24].

3.6 Antimalarial Chalcones

A class of secondary plant metabolites known as chalcones exhibits specific suppression of the malaria parasite Plasmodium falciparum. When given orally or intraperitoneally, licorice root-derived licochalcone A was shown to provide excellent protection against P. falciparum in mouse models[25]. It works by interfering with the parasite's mitochondria. Furthermore, erythrocytes are changed into echinocytes by the membrane-active substance licochalcone A, which makes the environment unsuitable for the parasite's proliferation. Crotaorixin, another chalcone that was isolated from Crotalaria orixensis, also exhibits potential for additional research[26].

3.7 Antibacterial Chalcone

Gram-positive bacteria are susceptible to the antibacterial properties of natural chalcones such as 3-deoxypanchalcone, bavachalcone, and licochalcones B, D, and E. With a wider range of activity, chalcones like phloridzin, licochalcone A, and isobavachalcone are effective against both Gram-positive and Gram-negative bacteria and fungi[27].

3.8 Chalcones possess antiviral properties

It does this by blocking important enzymes involved in the viral replication cycle, including neuraminidase, reverse transcriptase, and proteases. When viral resistance to traditional therapies arises, they are also being researched as potential substitutes[28]. Chalcones have the ability to reduce inflammation and regulate antiviral responses by activating the NRF2 transcription factor. Other chalcones, such as curcumin, quercetin, and myricetin, inhibit the dengue virus NS2b/NS3 protease, while isoliquiritigenin, which is produced from Glycyrrhiza spp., inhibits HSV, hepatitis C, and influenza A [29].

4. Molecular Targets of Chalcone-based Inhibitors in Cardiovascular diseases

Numerous molecular targets implicated in cardiovascular disorders have been found to be inhibited by chalcones and their derivatives. Diacylglycerol Acyltransferase (DGAT), Pancreatic Lipase (PL), Cholesteryl Ester Transfer Protein (CETP), ACE, calcium and potassium channels, triglyceride production, and Acyl-Coenzyme A: cholesterol acyltransferase (ACAT) are a few of these[30].A network mapping the interactions between chalcones and their corresponding therapeutic targets has been developed as a result of the expanding body of research.By altering the aromatic rings, substituting heteroaryl groups, or joining them with other pharmacologically active scaffolds, researchers are also creating new chalcone derivatives. These altered chalcones have the potential to treat obesity, arrhythmias, hypertension, and other cardiovascular issues[31].

4.1 Chalcones as Anti-Hypertensive Agents

High blood pressure is a hallmark of hypertension (HT), which can result in heart problems such myocardial infarction, stroke, and organ damage. It is divided into two categories: primary, which has no known etiology, and secondary, which is brought on by renal or endocrine problems. Current therapies focus on calcium channels, ACE, receptors, and electrolytes; however, safer, longer-acting, multi-targeted alternatives are required [32]. Chalcones may be useful in the treatment of hypertension, according to recent research. For instance, by preventing norepinephrine and angiotensin-induced contractions, the chalcone derivative R-2803 has demonstrated long-lasting antihypertensive benefits. Other chalcones, such as 2,4,6-trimethoxychalcone, decrease inflammation and the growth of vascular smooth muscle. Chalcones also support their potential as antihypertensive medicines by improving endothelial function through increased nitric oxide (NO) generation [33].

4.2 Chalcones as Angiotensin Converting Enzyme (ACE) Inhibitors

Hormones such as corticoids, estrogen, and thyroid hormones cause the liver to generate the α-globulin angiotensinogen, which is then released into the plasma [49]. The juxtaglomerular apparatus secretes an enzyme called renin, which cleaves it to form angiotensin I (AngI). The Angiotensin Converting Enzyme (ACE), which is found on the membranes of endothelial cells, subsequently transforms this further into Angiotensin II (AngII). The quick conversion of AngI to AngII, which causes vasoconstriction and aldosterone secretion and raises blood pressure, is facilitated by ACE [34]. ACE is linked to the cell membrane by a hydrophobic region and possesses a broad extracellular domain and a small intracellular tail. The rate at which AngII is produced is regulated by renin, which is released in reaction to low Na+ concentration. Vasoconstriction and salt retention eventually cause high blood pressure [35]. By blocking the conversion of AngI to AngII, inhibition of ACE breaks the cascade and lowers blood pressure [36]. Captopril and enalapril, two common ACE inhibitors, block the terminal leucine of AngI by attaching to the zinc atom in the enzyme's active site [37].

Figure1:List of chalcones as ACE inhibitors

4.3 Chalcones as Calcium Channel Blockers

Ischemic heart disease (IHD), also known as coronary heart disease (CHD), is a disorder in which the heart's coronary arteries narrow, preventing it from receiving enough oxygen-rich blood. Angina pectoris is one of the many consequences that result from this[38]. Agents that widen blood arteries are frequently used to treat IHD because they lower both preload (venous return) and afterload (arterial resistance). Calcium ion inflow drives the contraction of vascular smooth muscle. Calcium channel blockers encourage vasodilation and lower blood pressure by preventing this calcium influx [39]. In myocardial cells, sodium (Na+) and calcium (Ca2+) ions are involved in the depolarization and contraction processes. In muscle cells, calcium binds to troponin, promoting the actin-myosin connection necessary for contraction. Calcium causes calmodulin in vascular smooth muscle to become active, which causes the muscle to contract [40]. Vasodilation results from the reduction of this calcium influx caused by blocking calcium channels.

Figure 2.List of chalcones as calcium channel blockers.

4.4 Chalcones as Anti-Arrhythmic Agents

Common cardiovascular issues include arrhythmias, such as ventricular arrhythmias and atrial fibrillation. Ion channel blockers, β-blockers, and other antiarrhythmic medications are often used in current therapy; however, these medications may have adverse consequences. By altering ion channels, especially sodium and calcium channels, which are crucial for preserving healthy heart rhythm, chalcone derivatives have shown promise as antiarrhythmic drugs. Certain chalcones have been demonstrated to lessen cardiomyocytes' excessive action potential firing, which aids in the prevention of arrhythmias [41]. These substances may be safer and more efficient substitutes for current antiarrhythmic medications.

Figure3

4.5 Chalcones as Anti-Platelet Agents

Prostaglandin H2 is changed by thromboxane synthase (TX) into thromboxane A2 (TXA2), a crucial mediator of platelet aggregation and vasoconstriction that plays a role in diseases like myocardial infarction and stroke. Platelet aggregation is decreased and ischemia episodes are avoided by inhibiting TXA2 production. One class of flavonoids known to have the potential to inhibit TXA2 is chalcones. Research indicates that chalcones have the ability to suppress TXA2 release, ADP-induced aggregation, and cyclooxygenase-1 (COX-1). Compounds having particular substitutions, like 4-fluorophenyl or 2-furfuryl groups, have stronger inhibitory effects on TXA2. According to these results, chalcones may help stop excessive platelet aggregation and thrombus development.[42]

Figure4.List of chalcones as anti-platelet agents.

4.6. Chalcones in Hyperlipidemia Management

Cholesterol buildup causes atheromatous plaques to develop in arteries, which can obstruct blood flow by developing from fatty streaks to fibro-fatty lesions. Angina pectoris, thrombosis, and perhaps myocardial infarction (MI) or stroke result from this. Lipid levels and the risk of atherosclerosis are strongly correlated, according to research. Chalcone-based medications have been created to treat heart disease and hyperlipidemia by focusing on important lipid metabolism-related enzymes such DGAT, LPL, PL, CETP, and PPAR-α [43].

4.7 Chalcones as Inhibitors of Triglyceride (TG) Synthesis Dietary fats produce triglycerides (TGs), which are absorbed and stored in tissues for energy. Triacylglycerol (TAG) is produced in adipocytes by DGAT, which also converts glycerol-3-phosphate and Acyl-CoA. Increased lipolysis due to elevated TG levels increases the risk of atherosclerosis and coronary heart disease, which is made worse by poor lifestyle choices, smoking, high blood pressure, obesity, and mental health issues[44].

4.8 Chalcones as Diacylglycerol Acyltransferase (DGAT) Inhibitors:

The last stage of triglyceride (TG) production is carried out by DGAT, which transforms acyl-CoA and diacylglycerol into TGs. This mechanism is essential for the formation of adipose tissue and plays a role in the liver's synthesis of dietary TGs as well as their absorption in the small intestine. In adipose tissue, DGAT is also essential for the re-esterification and storage of TGs. [45] DGAT is a key target for anti-obesity therapies since it can lower the production of TG. Hops (Humulus lupulus) include compounds including xanthohumol and xanthohumol B, which have been demonstrated to efficiently suppress TG production in living cells and inhibit DGAT activity in rat liver microsomes with IC50 values of 50.3 and 194.0 μM, respectively[46].

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

4.9 Chalcones as Cholesteryl Ester Transfer Protein (CETP) Inhibitors

By converting triglycerides from VLDL or LDL into cholesteryl esters from HDL, CETP, a plasma protein, promotes the transfer of triglycerides and cholesteryl esters between lipoproteins and plays a critical role in lipid metabolism. By lowering LDL cholesterol and raising HDL cholesterol, CETP inhibition can lower the risk of atherosclerosis [47]. Hirata et al. looked into the CETP-inhibiting properties of a number of chalcones, such as xanthohumol and desmethylxanthohumol. With an IC50 of 88.0 μM, xanthohumol was determined to be the most potent CETP inhibitor [48]. The study found that xanthohumol's prenyl group at the A-ring is essential to its CETP inhibitory function, whereas the 6'-methoxy group may inhibit it. Remarkably, the precursor of xanthohumol, desmethylxanthohumol, had more action, underscoring the significance of the chalcone scaffold and its 3'-prenyl group in CETP inhibition [49].

4.10 Chalcones as Pancreatic Lipase (PL) Inhibitors

An enzyme called pancreatic lipase (PL) hydrolyzes triglycerides into monoglycerides and free fatty acids, which is essential for the digestion of fat. By reducing the absorption of dietary lipids, inhibition of PL limits the buildup of fat. Birari et al. investigated the glycosides of hydroxylated chalcones that were separated from the roots of Glycyrrhiza glabra, or licorice. With IC50 values ranging from 7.3 to 37.6 μM, they discovered that chalcones and their glycosidic derivatives both had strong PL inhibitory action. The chemical that established robust hydrogen bonds with important catalytic residues in the active site of the PL enzyme had the highest in silico docking score.In rats fed a high-fat diet, the chemical dramatically decreased body weight growth and plasma lipid levels in vivo, confirming the chalcone scaffold's potential as a PL inhibitor for the treatment of obesity [50].

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

4.11. Chalcones as Acyl-CoA: Cholesterol Acyltransferase (ACAT) Inhibitors

The enzyme ACAT is essential for the metabolism of cholesterol and the development of atherosclerosis because it converts free cholesterol into cholesteryl esters [51]. ACAT inhibition may be able to stop atherosclerosis and high cholesterol. Psoralea corylifolia's isobavachalcone was found by Choi et al. to be a strong ACAT inhibitor, with an IC50 of 48 μM. This chalcone is a viable candidate for additional development as an anti-hypercholesterolemia drug because it successfully decreased the synthesis of cholesteryl ester in HepG2 cells[52].

Figure 7

4.12 Chalcones as Lipoprotein Lipase (LPL) Activators

One of the main targets for the development of lipid-lowering treatments has been hyperlipoproteinemia, a disorder marked by increased lipid levels. Among the first medications to show lipid-lowering effects were fibrates, which raise lipoprotein lipase (LPL) activity. Using a hyperlipidemic rat model, Sashidhara et al. synthesized new chalcone-based fibrates and assessed their effects. In comparison to fenofibrate, indole-chalcone hybrids had notable anti-dyslipidemic benefits, lowering total cholesterol by 24–33%. Chalcone-fibrate hybrids may have better lipid-lowering potential than traditional treatments, as evidenced by the coumarin-chalcone hybrid's comparable results [53].

Figure 8 List of chalcones as Lipoprotein Lipase (LPL) activators

4.13 Miscellaneous Anti-Hyperlipidemic Chalcones

Several chalcone derivatives have shown potential in managing hyperlipidemia through various mechanisms:

Figure 9 List of miscellaneous anti-hyperlipidemic chalcones.

1. In hypertensive rats,4-hydroxyderricin (4-HD), which was isolated from Angelica keiskei Koiz, lowers liver triglycerides and raises HDL levels. Additionally, by reducing microsomal triglyceride transfer protein (MTP), it lowers VLDL levels, indicating that it may be used to treat increased liver and VLDL triglycerides [54].
2. Xanthoangelol: This substance lowers liver triglycerides and increases fecal cholesterol excretion, which lowers LDL and total cholesterol. It supports its function in lipid control by enhancing PPAR-α and important lipid metabolism-relatedenzymes[55].
3. Santos et al.'s investigation on chalcones revealed that chalcones such as 4',4-dichlorochalcone and 4'-chlorochalcone were more successful than lovastatin in decreasing cholesterol, triglycerides, and LDL-C in models of chronic hyperlipidemia, indicating their potential as lipid-lowering drugs [56].

4.14. Cardioprotective Effects of Chalcones

Chalcones have shown potential in protecting the heart from myocardial infarction (MI) and ischemia/reperfusion (I/R) injuries:

1. Halogenated Chalcones: Chalcones that have been substituted with fluorine and chlorine have cardioprotective qualities because they decrease lipid peroxidation and infarct size.
2. YLSC: This chalcone derivative protects the heart against MI by lowering apoptosis, infarct size, and myocardial damage indicators (AST, LDH)[57].

Other Cardiovascular Effects:

1. Neobavachalcone and 2-hydroxychalcone: Assist in preventing I/R damage and coronary atherosclerosis.
2. Isoliquiritigenin and licochalcone B: Provide protection against stroke and MI by blocking β-adrenergic transmission.
3. Glypallichalcone and Licochalcone A: By blocking both α- and β-receptors, they protect the cardiovascular system.
4. Licochalcone G: By blocking coagulation factor Xa, it prevents thromboembolic episodes[58].

Figure 10 List of miscellaneous chalcones with cardiovascular activity.

Several of these chalcones also exhibit anti-obesity effects, further underscoring their broad spectrum of cardiovascular and metabolic benefits [59].These results demonstrate the substantial therapeutic potential of chalcones in the treatment of metabolic and cardiovascular disorders, with several chalcones demonstrating promise in blood pressure management, cholesterol reduction, and heart damage prevention[60].

5. Various Synthetic Methods

The following provides a summary of various synthetic approaches to chalcone derivatives, focusing on the different reaction conditions and substrates used in their preparation:

1 General method for synthesis of chalcone Derivative 1:

In a conical flask, add 3.0g of substituted benzaldehyde to a solution of substituted ketone (0.025 mole) that has been agitated in 8 mL of ethanol. Drop by drop, add 4 mL of 30% NaOH. In an ice-cold water bath, the mixture is swirled until it freezes [61]. Following an overnight period of cold storage, the hardened material separated and dried at ambient temperature. Chalcone crystals recrystallize when exposed to aqueous ethanol. Plan 1

2. General method for synthesis of chalcone derivative II:

50 milliliters of ethanol dissolve a mixture of substituted chalcone (10 mmol), urea, thiourea, and hydrazine hydrate 2, 4-dinitrophenyl hydrazine. Drops of HCl should be added. The liquid must reflux for four hours before being poured and kept in crushed ice. [62]. The precipitate is filtered, allowed to dry at room temperature, and then recrystallized from ethanol. Scheme 2 for Chalcone Derivative II

3. General method for synthesis of chalcone derivative III:

After being heated in a reflux condenser for six hours, a combination of 0.01 mol urea, 1 gm KOH, and 0.01 mol of necessary chalcone in 20 ml of ethanol was cooled, poured over crushed ice, and the collected solid product was filtered. After 30 minutes of standing in a cold bath, recrystallization took place [63], after which the material was filtered and dried. Plan 3

General Reaction Mechanism

4. Synthesis of Chalcone Derivatives from 2-Acetyl Naphthalene:

Benzaldehyde or substituted benzaldehydes were reacted with 2-acetyl naphthalene in methanol, with potassium hydroxide serving as the base, to create chalcones 1a−g. These compounds' antifungal and antibacterial qualities were assessed[64].

Scheme 4. Synthesis of Chalcones

Reaction Mechanism

5. Chalcone Derivatives with Triazine Substitution:

Aniline and cyanuric acid were reacted at regulated low temperatures to produce a series of trisubstituted triazines (6a–f), which were then followed by reactions with substituted amines and 4-aminoacetophenone. The matching chalcone derivatives were then created by reacting these triazines with different aldehydes [65].

Scheme 5. Synthesis of Triazines 6a−f Containing Chalcone

Reaction Mechanism

6. Acetamido Chalcone Derivatives:

By reacting 4-acetamidoacetophenone with substituted aldehydes in potassium hydroxide and ethanol under ultrasonic conditions, a rapid and effective reaction was produced, leading to the synthesis of chalcone derivatives 10a–f. [66]

Scheme 6. Synthesis of Chalcones

Reaction Mechanism

7. Methoxyamino Chalcones:

A Claisen-Schmidt condensation reaction involving acetophenone and benzaldehyde derivatives in ethanol with 40% NaOH under mild reaction conditions was used to create chalcones [67].

Scheme 7. Synthesis of Chalcones Derivatives

Reaction Mechanism

8. Sappan Chalcones:

A Claisen-Schmidt reaction using benzaldehyde and acetophenone derivatives, followed by ultrasonic irradiation in methanol with potassium hydroxide, was used to create chalcone derivatives[68].

Scheme 8. Construction of Chalcone Derivatives a

Reagents and conditions: (a) KOH aq , MeOH, ultrasound-assisted; (b) KOH aq , ultrasound-assisted

Scheme 9. Synthesis of Sappanchalcone

Reagents and conditions: (a) CH3COOH, polyphosphoric acid, 60 °C, 30 min; (b) 2′,4′-dihydroxyacetophenone, 12 M KOH, ultrasound assisted, 80 °C, 8 h.

Reaction Mechanism

9. Synthesis from 1,3-Diacetylbenzene:

Chalcone derivatives was produced by catalyzing the condensation of 1,3- and 1,4-diacetylbenzene with 4-hydroxy-3-methoxybenzaldehyde using an acid. It was found that sulfuric acid concentrated in ethanol was the most effective catalyst [69].

Strategy 10

Reagents and conditions: (a) H 2 H 2 SO 4 SO 4, 1,3-diacetylbenzene, ethyl alcohol, reflux, 3 h; (b) H , 1,3,5-triacetylbenzene, reflux, 3 h

Reaction Mechanism

10. Chalcones from 1-(2′,4′-Difluorobiphenyl-4-yl) ethanone:

Chalcone derivatives 50a−d were created by reacting 1-(2′,4′-difluorobiphenyl-4-yl) ethenone with different aldehydes in 40% NaOH using a solvent-free Claisen-Schmidt condensation [70].

Scheme 11. Synthesis of (E)-1-(2′,4′-Difluorobiphenyl-4-yl)-3-arylprop-2-en-1-ones

Reaction Mechanism

11. Synthesis of Chalcone from Acetophenone Derivatives:

Chalcones with yields ranging from 93% to 97% were produced when hydroxyacetophenones reacted with a benzaldehyde derivative in 50% KOH. Chalcone, on the other hand, was produced with KOH as the catalyst at a lesser yield of 32%. However, employing BF?·Et?O as the catalyst, chalcone B was produced with remarkable efficiency (90% yield). Veratraldehyde and 4-hydroxyacetophenone reacted to produce chalcone 54 with a high yield of 97%[71] .Chalcones 55 and 56 were also generated by treating 2,4-dihydroxyacetophenone, with yields of 96% and 93%, respectively. (Plan 12)

Reaction Mechanism

Aldehyde and acetophenone were reacted in ethanol with 40% NaOH or a few drops of hydrochloric acid to create chalcone derivatives [72]. (Scheme 13)

Additionally, chalcone was formed when benzaldehyde and acetophenone derivatives were treated in a liquid solvent at temperatures ranging from 50 to 100°C in an acidic or alkaline environment [73].

 Scheme 14. Claisen−Schmidt Condensation

12. Chalcone Formation via Phenyl Halide:

Chalcone was prepared by reaction of phenyl halide and styrene in carbon monoxide and pd catalyst [74]. (Scheme15).

The required chalcone 99 was produced by treating phenylacetylene with benzaldehyde in Bmim OTs (1-butyl-3-methylimidazolium tosylate) and HBr at 100°C for 12 hours[75]. Scheme 16 describes the coupling mechanism that drives the reaction.

Reaction Mechanism

Propargyl alcohol and phenyl halide reacted under microwave radiation to create a chalcone derivative. With tetrahydrofuran (THF) acting as the solvent, the catalyst PdCl?(PPh?)? aided the reaction[76]. By speeding up the process, microwave energy provides a more effective way to generate chalcone derivatives. Plan 17.

13. Chalcone Synthesis Using Benzoyl Chlorides: Synthesis of Ynones:

Sonogashira coupling conditions are used to react benzoyl chlorides with phenylacetylenes to create ynones. Usually, a palladium-based catalyst (like Pd (PPh?)?) and a base, like CsCO? in anhydrous toluene, are present for this reaction to occur[77]. After ynones are synthesized, they are deuterated utilizing the H-Cube technique, in which ordinary water is substituted with deuterium oxide (D?O). Deuterium can be added to the chemical at this phase, which is especially helpful for mechanism studies or for making some molecules more stable[78].

Scheme 18: This represents the process for ynone synthesis.

Reaction Mechanism

2. Synthesis of Chalcone Derivatives:

Benzoyl chloride and styrylboronic acid can react to create chalcones, for example. Using Pd(PPh?)? as the catalyst and CsCO? as the base, this reaction is conducted in anhydrous toluene. The Suzuki-Miyaura coupling mechanism, which is well-known for its effectiveness in creating carbon-carbon bonds, drives the reaction [79]. A different method for synthesizing chalcones is to react cinnamoyl chloride with phenylboronic acid under Suzuki-Miyaura conditions. This reaction, like the one before it, uses Pd(PPh?)? and CsCO? in anhydrous toluene[80].

Scheme 19: This scheme illustrates the Suzuki-Miyaura coupling used in chalcone formation.

14. One-Pot Chalcone Synthesis Phenylmethanol (105) was reacted with acetophenone using CrO? as the oxidizing agent, resulting in the formation of chalcone derivative. Scheme 20

In a different process, 1,2-dichloroethane was used as the solvent and benzaldehyde and phenylacetylene were microwave-irradiated in a catalytic amount using a heterogeneous acid catalyst[81]. The matching chalcone was likewise formed by this reaction. Plan 21

15. Chalcones from Natural Products: Naturally occurring Chalcones found in plants such as Macaranga denticulata, Uvaria siamensis, Stevia lucida, and Pongamia pinnata. Additionally, hydroxychalcones with sugar functionalities were isolated from Coreopsis lanceolata flowers[82].