Chalcones

• Antioxidant
• Anti-inflammatory
• Anticancer properties
• Antimicrobial

• Neuroprotection
• Cardiovascular support
• Antidiabetic effects
• Immunomodulation
• Hepatoprotection

Chalcones are a class of open-chain flavonoids characterized by two aromatic rings connected by a three-carbon α,β-unsaturated carbonyl system. This unique chemical structure, featuring the 1,3-diphenyl-2-propen-1-one scaffold, contributes to their diverse biological activities. Chalcones serve as precursors in the biosynthesis of flavonoids and isoflavonoids in plants and are produced as part of the plant’s defense mechanism against environmental stressors. The biological activities and mechanisms of action of chalcones are diverse and often structure-dependent, with different substitution patterns on the aromatic rings leading to varying potencies and specificities.

One of the most significant mechanisms of chalcones is their potent antioxidant activity. The α,β-unsaturated carbonyl group, along with hydroxyl substituents on the aromatic rings (particularly at positions 2′ and 4′), enables chalcones to scavenge reactive oxygen species (ROS) and free radicals through hydrogen atom donation. Chalcones can also chelate metal ions (such as iron and copper) that catalyze oxidative reactions, thereby preventing the formation of ROS. Additionally, many chalcones activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of cellular antioxidant defenses.

Under normal conditions, Nrf2 is bound to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, which targets it for ubiquitination and degradation. Chalcones can modify the cysteine residues of Keap1 through Michael addition reactions, disrupting the Keap1-Nrf2 interaction and allowing Nrf2 to translocate to the nucleus. In the nucleus, Nrf2 binds to antioxidant response elements (AREs) in the promoter regions of target genes, inducing the expression of antioxidant and detoxifying enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), and γ-glutamylcysteine synthetase (γ-GCS). Chalcones demonstrate significant anti-inflammatory effects through multiple pathways, with inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway being particularly important.

In the canonical NF-κB pathway, inflammatory stimuli activate the IκB kinase (IKK) complex, which phosphorylates inhibitor of κB (IκB) proteins, leading to their ubiquitination and degradation. This releases NF-κB dimers, allowing them to translocate to the nucleus and induce the expression of pro-inflammatory genes. Chalcones can inhibit this pathway at multiple points: they can prevent the activation of the IKK complex, inhibit the phosphorylation and degradation of IκB, and directly interfere with the DNA-binding activity of NF-κB. Through these mechanisms, chalcones suppress the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (MCP-1, IL-8), adhesion molecules (ICAM-1, VCAM-1), and enzymes involved in inflammation (COX-2, iNOS).

Chalcones also modulate other inflammatory signaling pathways, including the mitogen-activated protein kinase (MAPK) cascades (p38 MAPK, ERK, JNK) and the JAK-STAT pathway. Additionally, some chalcones inhibit the activity of pro-inflammatory enzymes such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and microsomal prostaglandin E synthase-1 (mPGES-1), reducing the production of inflammatory mediators like prostaglandins and leukotrienes. In cancer biology, chalcones exhibit anticancer properties through multiple mechanisms. They induce cell cycle arrest, primarily at the G2/M phase, by modulating the expression and activity of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (p21, p27).

Chalcones trigger apoptosis (programmed cell death) in cancer cells through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways. In the intrinsic pathway, chalcones increase the expression of pro-apoptotic proteins (Bax, Bad) and decrease the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL), leading to mitochondrial membrane permeabilization, cytochrome c release, and caspase activation. In the extrinsic pathway, chalcones can upregulate death receptors (Fas, TRAIL receptors) and their ligands, initiating the caspase cascade. Chalcones also inhibit angiogenesis (formation of new blood vessels) by downregulating vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α), thereby limiting tumor growth and metastasis.

Additionally, they suppress cancer cell migration and invasion by inhibiting matrix metalloproteinases (MMPs) and modulating epithelial-mesenchymal transition (EMT) markers. Some chalcones demonstrate epigenetic effects, including inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), potentially reversing aberrant epigenetic modifications in cancer cells. Chalcones possess significant antimicrobial properties against a wide range of pathogens, including bacteria, fungi, viruses, and parasites. Their antimicrobial mechanisms include disruption of cell membranes, inhibition of cell wall synthesis, interference with nucleic acid synthesis, and inhibition of energy metabolism.

The α,β-unsaturated carbonyl group can react with nucleophilic groups in microbial proteins and enzymes, disrupting their function. Some chalcones specifically target bacterial type III secretion systems, quorum sensing mechanisms, or biofilm formation. In metabolic regulation, chalcones demonstrate antidiabetic effects through multiple mechanisms. They enhance insulin sensitivity by activating peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates glucose metabolism and insulin sensitivity.

They also activate adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle and liver, leading to increased glucose uptake, enhanced glycolysis, and reduced gluconeogenesis. Some chalcones inhibit α-glucosidase and α-amylase, enzymes involved in carbohydrate digestion, thereby reducing postprandial glucose spikes. Additionally, chalcones can protect pancreatic β-cells from oxidative stress and inflammation, potentially preserving insulin secretion capacity. In cardiovascular health, chalcones improve endothelial function by increasing nitric oxide (NO) production through activation of endothelial nitric oxide synthase (eNOS).

They also demonstrate vasodilatory effects and inhibit platelet aggregation and thrombus formation, potentially reducing the risk of thrombotic events. Additionally, they improve lipid profiles by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides while increasing high-density lipoprotein (HDL) cholesterol. Some chalcones inhibit the oxidation of LDL, a key step in atherosclerosis development. In neurological function, chalcones demonstrate neuroprotective effects through multiple mechanisms.

They protect neurons from oxidative stress and inflammation, which are key factors in neurodegenerative diseases. They modulate neurotransmitter systems, potentially affecting mood, cognition, and stress responses. Some chalcones inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes that break down acetylcholine, potentially enhancing cholinergic neurotransmission in conditions like Alzheimer’s disease. Additionally, they may inhibit the aggregation of amyloid-β and tau proteins, key pathological features of Alzheimer’s disease.

The pharmacokinetics of chalcones are complex and influenced by various factors. After oral administration, chalcones are absorbed in the intestine, though their bioavailability is generally low due to limited solubility, extensive first-pass metabolism, and potential efflux by transporters like P-glycoprotein. In the liver, chalcones undergo phase I metabolism (primarily hydroxylation by cytochrome P450 enzymes) and phase II metabolism (glucuronidation, sulfation, and glutathione conjugation), forming metabolites that are more water-soluble and readily excreted in urine. The plasma half-life of chalcones is relatively short, typically ranging from 1-8 hours depending on the specific compound and its substitution pattern.

The biological effects of chalcones are thus a combination of their direct actions through multiple mechanisms, with their antioxidant, anti-inflammatory, and anticancer activities being particularly significant for their potential health benefits.

Optimal dosage ranges for chalcones are not well-established due to limited clinical studies specifically evaluating chalcones as supplements. Most research has been conducted in preclinical settings (cell culture and animal models) or with plant extracts containing chalcones along with other bioactive compounds. Based on the available research and considering the diverse nature of chalcones, the following dosage ranges can be considered: For licorice root extract (standardized to contain chalcones such as isoliquiritigenin), typical dosages range from 250-500 mg daily, corresponding to approximately 2.5-10 mg of total chalcones. For citrus peel extract (standardized to contain chalcones such as naringenin chalcone), typical dosages range from 500-1000 mg daily, corresponding to approximately 5-20 mg of total chalcones.

For turmeric extract (containing curcumin, which has a chalcone-like structure), typical dosages range from 500-2000 mg daily, though the chalcone content varies significantly depending on the extraction and standardization methods. For isolated chalcones (rare as commercial supplements), the estimated dosage range is 5-50 mg daily, though this is primarily based on preclinical studies and limited human data. It’s important to note that different chalcones have varying potencies and biological activities, so optimal dosages may vary depending on the specific chalcone or chalcone-containing extract. Additionally, the bioavailability of chalcones is generally low, which may necessitate higher doses or enhanced delivery formulations for therapeutic effects.

For most health applications, starting with a lower dose and gradually increasing as needed and tolerated is recommended. Divided doses (2-3 times daily) may be preferred due to the relatively short half-life of most chalcones, though specific pharmacokinetic data in humans is limited for many chalcones.

Chalcones generally have low to moderate oral bioavailability, typically ranging from 5-20% depending on the specific compound and formulation, though comprehensive human pharmacokinetic data is lacking for many chalcones. Several factors contribute to this limited bioavailability. Chalcones have poor water solubility due to their hydrophobic aromatic rings, which limits their dissolution in the gastrointestinal fluid. The compounds undergo extensive first-pass metabolism in the intestine and liver, primarily through phase I (hydroxylation) and phase II (glucuronidation, sulfation, and glutathione conjugation) reactions, which significantly reduce the amount of free chalcones reaching the systemic circulation.

Additionally, chalcones may be subject to efflux by intestinal transporters such as P-glycoprotein, further limiting their absorption. The α,β-unsaturated carbonyl group in chalcones can also react with nucleophilic groups in proteins and other biomolecules, potentially reducing the amount of free compound available for absorption. The absorption of chalcones occurs primarily in the small intestine through passive diffusion, facilitated by their moderate lipophilicity. Some evidence suggests that certain chalcones may be absorbed via active transport mechanisms, though the specific transporters involved have not been fully characterized.

After absorption, chalcones undergo extensive metabolism in the intestinal epithelium and liver. Phase I metabolism primarily involves hydroxylation by cytochrome P450 enzymes, particularly CYP1A2, CYP2C9, and CYP3A4. Phase II metabolism involves conjugation with glucuronic acid (glucuronidation), sulfate (sulfation), and glutathione, forming conjugates that are more water-soluble and readily excreted in urine. These conjugates may be less biologically active than free chalcones, though some evidence suggests they can be deconjugated in target tissues, releasing the active compounds.

The plasma half-life of chalcones is relatively short, typically ranging from 1-8 hours depending on the specific compound and its substitution pattern, necessitating multiple daily doses for sustained therapeutic effects. Chalcones demonstrate moderate distribution to various tissues, with some evidence suggesting they can cross the blood-brain barrier to some extent, which is particularly relevant for their potential neuroprotective effects. The bioavailability of chalcones is influenced by various factors, including food matrix, processing methods, and individual factors such as gut microbiome composition, intestinal transit time, and genetic factors affecting metabolic enzymes. Consumption with a high-fat meal may enhance the absorption of chalcones by increasing bile secretion and improving their solubilization, though excessive fat may reduce absorption by slowing gastric emptying.

Certain food components, such as piperine from black pepper, may enhance the bioavailability of chalcones by inhibiting efflux transporters and metabolic enzymes.

Liposomal formulations – can increase bioavailability by 3-5 fold by enhancing cellular uptake and protecting chalcones from degradation, Nanoemulsion formulations – can increase bioavailability by 4-6 fold by improving solubility and enhancing intestinal permeability, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, potentially increasing bioavailability by 3-5 fold, Phospholipid complexes – enhance lipid solubility and membrane permeability, potentially increasing bioavailability by 2-4 fold, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, potentially increasing bioavailability by 2-3 fold, Solid dispersion techniques – enhance dissolution rate and solubility, potentially increasing bioavailability by 2-3 fold, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, potentially increasing bioavailability by 30-60%, Microemulsions – provide a stable delivery system with enhanced solubility, potentially increasing bioavailability by 3-5 fold, Co-administration with fatty meals – can increase absorption by stimulating bile secretion and enhancing lymphatic transport, potentially increasing bioavailability by 20-50%, Structural modifications – addition of hydrophilic groups or prodrug approaches can improve solubility and stability, potentially increasing bioavailability by 50-200%

Chalcones are best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. However, extremely high-fat meals should be avoided as they may slow gastric emptying and potentially reduce absorption. Due to the relatively short half-life of most chalcones (typically 1-8 hours depending on the specific compound), divided doses (2-3 times daily) may be beneficial for maintaining consistent blood levels throughout the day, though specific human pharmacokinetic data is limited for many chalcones. For antioxidant and anti-inflammatory effects, consistent daily dosing is recommended, with some evidence suggesting that divided doses throughout the day may provide more continuous protection against oxidative stress and inflammation.

Taking chalcones with meals may also help reduce postprandial oxidative stress and inflammation, which are associated with various chronic diseases. For cardiovascular support, consistent daily dosing is recommended, with some evidence suggesting that taking chalcones with meals may help reduce postprandial oxidative stress and inflammation, which are risk factors for cardiovascular disease. For metabolic regulation and diabetes support, taking chalcones with meals may help reduce postprandial glucose spikes by inhibiting carbohydrate-digesting enzymes and enhancing insulin sensitivity. Some evidence suggests that taking chalcones 15-30 minutes before meals may be particularly beneficial for this purpose, though more research is needed.

For neuroprotection, consistent daily dosing is recommended, with some evidence suggesting that evening dosing may enhance neuroprotective effects during sleep, though more research is needed. For antimicrobial support, consistent daily dosing is recommended, with some evidence suggesting that taking chalcones between meals may enhance their antimicrobial effects by reducing competition with food components, though more research is needed. Enhanced delivery formulations like liposomes or nanoemulsions may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food for optimal absorption. The timing of chalcone supplementation relative to other medications should be considered, as chalcones may interact with certain drugs, particularly those metabolized by the same enzymes or transported by the same transporters.

In general, separating chalcone supplementation from other medications by at least 2 hours is recommended to minimize potential interactions.

• Gastrointestinal discomfort (mild to moderate, common)
• Nausea (uncommon)
• Headache (uncommon)
• Allergic reactions (rare, particularly in individuals with allergies to plants containing chalcones)
• Mild dizziness (rare)
• Skin rash (rare)
• Mild insomnia (rare)
• Fatigue (uncommon)
• Altered taste sensation (rare)
• Photosensitivity (rare, particularly with certain chalcones)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Individuals with known allergies to plants containing chalcones (such as licorice, citrus, or turmeric)
• Individuals scheduled for surgery (discontinue 2 weeks before due to potential effects on blood clotting)
• Children and adolescents (due to insufficient safety data)
• Individuals with severe liver disease (due to potential effects on liver enzymes)
• Individuals with hormone-sensitive conditions (some chalcones may have estrogenic or anti-estrogenic effects)
• Individuals with bleeding disorders (some chalcones may have antiplatelet effects)
• Individuals with hypertension (particularly with licorice root extract due to potential glycyrrhizin content)
• Individuals with kidney disease (particularly with licorice root extract due to potential effects on electrolyte balance)
• Individuals with known hypersensitivity to chalcones or related compounds

• Anticoagulant and antiplatelet medications (may enhance antiplatelet effects, potentially increasing bleeding risk)
• Cytochrome P450 substrates (may affect the metabolism of drugs that are substrates for CYP1A2, CYP2C9, and CYP3A4)
• Antidiabetic medications (may enhance blood glucose-lowering effects, potentially requiring dose adjustment)
• Antihypertensive medications (particularly with licorice root extract due to potential glycyrrhizin content)
• Hormone replacement therapy and hormonal contraceptives (some chalcones may have estrogenic or anti-estrogenic effects)
• Immunosuppressants (potential interaction due to immunomodulatory effects)
• Drugs metabolized by UDP-glucuronosyltransferases (UGTs) (potential competition for these enzymes)
• Drugs with narrow therapeutic indices (warfarin, digoxin, etc.) require careful monitoring due to potential interactions
• Diuretics (particularly with licorice root extract due to potential effects on electrolyte balance)
• Corticosteroids (particularly with licorice root extract due to potential glycyrrhizin content)

Based on limited studies and considering the diverse nature of chalcones, the upper limit for chalcone supplementation is generally considered to be 50 mg daily for most adults when using isolated chalcones. For chalcone-containing extracts, upper limits should be calculated based on their chalcone content to avoid exceeding 50 mg of total chalcones daily. For licorice root extract, additional considerations apply due to the potential presence of glycyrrhizin, which can cause adverse effects at high doses. The European Scientific Committee on Food recommends limiting glycyrrhizin intake to 100 mg/day, which corresponds to approximately 600-1000 mg of licorice root extract depending on its glycyrrhizin content.

Higher doses may significantly increase the risk of side effects and drug interactions, particularly in sensitive individuals. For general supplementation, doses exceeding these levels are not recommended without medical supervision. The safety profile of chalcones warrants attention due to their diverse biological activities and potential for interactions with drugs and endogenous compounds. While many chalcones demonstrate favorable safety profiles in preclinical studies, comprehensive human safety data is lacking for many compounds in this class.

The α,β-unsaturated carbonyl group in chalcones can react with nucleophilic groups in proteins and other biomolecules, potentially leading to off-target effects or allergic reactions in sensitive individuals. This reactive group is also responsible for many of the beneficial effects of chalcones, highlighting the balance between therapeutic activity and potential toxicity. The long-term safety of chalcone supplementation has not been fully established, with most safety data derived from preclinical studies and limited human trials. Acute toxicity studies in animals have generally shown relatively low toxicity for many chalcones, with no significant adverse effects observed at doses equivalent to several times the recommended human doses.

However, the potential for cumulative effects with long-term use remains a consideration. The diverse nature of chalcones, with different substitution patterns leading to varying biological activities, adds complexity to safety considerations. Some chalcones may have hormonal effects (estrogenic or anti-estrogenic), while others may affect blood clotting, blood pressure, or glucose metabolism. These effects may be beneficial in certain contexts but potentially problematic in others, depending on individual health status and concurrent medications.

The safety of chalcones during pregnancy and breastfeeding has not been established, and their potential effects on fetal development or lactation raise concerns. Therefore, chalcone supplementation is not recommended during these periods. For most individuals, obtaining chalcones through moderate consumption of chalcone-containing foods (such as licorice, citrus fruits, tomatoes, and turmeric) as part of a balanced diet is likely safer than isolated chalcone supplements, as food sources provide lower amounts and contain other compounds that may modulate their effects.

Chalcones as a class of compounds are not specifically regulated by the FDA. Individual chalcones are not approved as drugs and are not generally available as standalone dietary supplements. Chalcone-containing plant extracts (such as licorice root extract, citrus peel extract, or turmeric extract) are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this framework, manufacturers are responsible for ensuring the safety of their products before marketing, but pre-market approval is not required.

Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of chalcones specifically. For licorice root extract, the FDA has issued specific guidance regarding glycyrrhizin content due to potential adverse effects at high doses, including hypertension, hypokalemia, and edema. While this guidance does not specifically address chalcones in licorice, it is relevant for licorice-derived chalcone supplements.

Synthetic chalcone derivatives being developed as pharmaceutical drugs would be regulated as new drug entities and would require full FDA approval through the standard drug development and approval process, including clinical trials demonstrating safety and efficacy.

Eu: Chalcones as a class of compounds are not specifically regulated in the European Union. Chalcone-containing plant extracts are primarily regulated as food supplements under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has evaluated several health claims related to plants containing chalcones (such as licorice and turmeric) and has generally not found sufficient evidence to approve specific claims. For licorice, the European Commission has established an upper limit for glycyrrhizin consumption at 100 mg/day, which is relevant for licorice-derived chalcone supplements. Synthetic chalcone derivatives being developed as pharmaceutical drugs would be regulated under the centralized procedure by the European Medicines Agency (EMA) or through national authorization procedures.

Uk: Chalcones as a class of compounds are not specifically regulated in the United Kingdom. Chalcone-containing plant extracts are regulated as food supplements. They are not licensed as medicines and cannot be marketed with medicinal claims. The Medicines and Healthcare products Regulatory Agency (MHRA) has not issued specific guidance on chalcones. For licorice, the UK follows similar guidance to the EU regarding glycyrrhizin content.

Canada: Chalcones as a class of compounds are not specifically regulated in Canada. Chalcone-containing plant extracts are regulated as Natural Health Products (NHPs) under the Natural Health Products Regulations. Several products containing licorice root extract, citrus peel extract, or turmeric extract have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims. Health Canada has established a maximum daily dose of 5 g of licorice root (corresponding to approximately 75-100 mg of glycyrrhizin) for oral use, which is relevant for licorice-derived chalcone supplements.

Australia: Chalcones as a class of compounds are not specifically regulated in Australia. Chalcone-containing plant extracts are regulated as complementary medicines by the Therapeutic Goods Administration (TGA). Several products containing licorice root extract, citrus peel extract, or turmeric extract are listed on the Australian Register of Therapeutic Goods (ARTG). The TGA has established a maximum daily dose of 5 g of licorice root (corresponding to approximately 75-100 mg of glycyrrhizin) for oral use, which is relevant for licorice-derived chalcone supplements.

Japan: Chalcones as a class of compounds are not specifically regulated in Japan. Chalcone-containing plant extracts may be regulated as Foods for Specified Health Uses (FOSHU) if they meet specific criteria and have supporting evidence for their health claims. The Ministry of Health, Labour and Welfare has not issued specific guidance on chalcones. For licorice, Japan follows similar guidance to other countries regarding glycyrrhizin content.

China: Chalcones as a class of compounds are not specifically regulated in China. Chalcone-containing plant extracts may be regulated as health foods and would require approval from the China Food and Drug Administration (CFDA) before marketing with health claims. Many chalcone-containing plants, such as licorice and turmeric, are also used in traditional Chinese medicine and are regulated under the traditional Chinese medicine framework.

Korea: Chalcones as a class of compounds are not specifically regulated in South Korea. Chalcone-containing plant extracts may be regulated as health functional foods and would require approval from the Ministry of Food and Drug Safety (MFDS) before marketing with health claims. For licorice, Korea follows similar guidance to other countries regarding glycyrrhizin content.

Medium

Isolated chalcones are not typically available as consumer supplements but are primarily used in research settings. Research-grade chalcones (>95% purity) typically cost $100-$500 per gram depending on the specific compound, making them prohibitively expensive for regular supplementation. Licorice root extract (standardized to contain chalcones such as isoliquiritigenin) typically costs $0.30-$1.00 per day for basic extracts (250-500 mg daily, corresponding to approximately 2.5-10 mg of total chalcones) and $1.00-$2.00 per day for premium, standardized formulations. Citrus peel extract (standardized to contain chalcones such as naringenin chalcone) typically costs $0.50-$1.50 per day for basic extracts (500-1000 mg daily, corresponding to approximately 5-20 mg of total chalcones) and $1.50-$3.00 per day for premium, standardized formulations.

Turmeric extract (containing curcumin, which has a chalcone-like structure in its enol form) typically costs $0.50-$2.00 per day for basic extracts (500-2000 mg daily) and $2.00-$5.00 per day for premium, standardized formulations or enhanced delivery systems. Enhanced delivery formulations (such as liposomes, nanoemulsions, or phospholipid complexes) typically cost $3.00-$8.00 per day, though these may provide improved bioavailability that could justify the higher cost.

The value of chalcone supplementation varies significantly depending on the specific health application, the form of supplementation, and individual factors. For antioxidant and anti-inflammatory support, chalcones offer moderate value. Preclinical studies have demonstrated potent antioxidant and anti-inflammatory effects through multiple mechanisms, including NF-κB inhibition and Nrf2 activation. For individuals with inflammatory conditions or high oxidative stress, chalcone-containing extracts may provide valuable support, particularly when combined with lifestyle modifications.

When compared to other natural antioxidants and anti-inflammatory compounds, chalcone-containing extracts are moderately priced and offer a reasonable option for general support. For cardiovascular support, chalcones offer moderate value. Preclinical studies have demonstrated beneficial effects on vascular function, lipid profiles, and inflammation, which are important factors in cardiovascular health. For individuals with cardiovascular risk factors, chalcone-containing extracts may provide valuable support, particularly when combined with lifestyle modifications and conventional treatments as needed.

When compared to other natural compounds for cardiovascular health, chalcone-containing extracts are moderately priced and offer a reasonable option for general support. For metabolic regulation and diabetes support, chalcones offer moderate to high value. Preclinical studies have demonstrated significant effects on insulin sensitivity, glucose metabolism, and adipokine production through multiple mechanisms. For individuals with insulin resistance, prediabetes, or type 2 diabetes, chalcone-containing extracts may provide valuable metabolic support, particularly when combined with lifestyle modifications and conventional treatments as needed.

When compared to other natural compounds for metabolic health, chalcone-containing extracts are moderately priced and offer a reasonable option for general support. For antimicrobial support, chalcones offer moderate value. Preclinical studies have demonstrated antimicrobial effects against various pathogens, including bacteria, fungi, and viruses. For individuals seeking natural antimicrobial support, chalcone-containing extracts may provide valuable assistance, particularly as a complementary approach alongside conventional treatments when needed.

When compared to other natural antimicrobial compounds, chalcone-containing extracts are moderately priced and offer a reasonable option for general support. When comparing the cost-effectiveness of different sources of chalcones: Whole food sources (such as licorice root, citrus fruits, and turmeric) offer the best value for general health maintenance, providing chalcones along with other beneficial nutrients and phytochemicals. However, the chalcone content can vary significantly based on growing conditions, processing, and storage. Standardized extracts offer a more reliable source of chalcones with consistent dosing, though at a higher cost.

These may be preferred for specific health applications where consistent dosing is important. Enhanced delivery formulations offer improved bioavailability, which may justify their higher cost for individuals with absorption issues or those seeking maximum therapeutic effects. However, the cost-benefit ratio should be carefully considered, as the improvement in bioavailability may not always justify the significantly higher cost. For most individuals, a balanced approach combining moderate consumption of chalcone-rich foods with standardized extracts as needed for specific health concerns may offer the best value.

This approach provides the nutritional benefits of whole foods while ensuring consistent dosing of chalcones for therapeutic effects when needed.

Pure chalcones have moderate stability, with a typical shelf life of 1-2 years when properly stored at -20°C under inert gas. At room temperature, their stability is significantly reduced, with a shelf life of approximately 3-6 months when protected from light, heat, and moisture. The α,β-unsaturated carbonyl group in chalcones is particularly susceptible to oxidation and Michael addition reactions, which can lead to degradation. Different chalcones have varying stability profiles depending on their specific substitution patterns.

Hydroxylated chalcones (such as isoliquiritigenin) tend to be less stable than methoxylated chalcones (such as licochalcone A) due to the greater susceptibility of hydroxyl groups to oxidation. Prenylated chalcones (such as xanthohumol) may have reduced stability due to the reactivity of the prenyl group. Standardized extracts containing chalcones (such as licorice root extract, citrus peel extract, or turmeric extract) typically have a shelf life of 1-2 years from the date of manufacture when properly stored in airtight, opaque containers at room temperature or below. The stability of chalcones in these extracts may be enhanced by the presence of other compounds with antioxidant properties.

In liquid formulations (such as tinctures or liquid extracts), chalcones have reduced stability compared to solid forms, with a typical shelf life of 6-12 months when properly stored in airtight, opaque containers. The presence of alcohol in these formulations may help preserve chalcones by inhibiting microbial growth and providing some protection against oxidation. Enhanced delivery formulations (such as liposomes, nanoemulsions, or phospholipid complexes) may have different stability profiles depending on the specific formulation. These formulations often provide some protection against degradation, potentially extending the shelf life of chalcones, but they may also introduce additional stability considerations related to the delivery system itself.

For pure chalcones (primarily used in research), storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability. Protect from light, heat, oxygen, and moisture, which can accelerate degradation. For standardized extracts containing chalcones, store in airtight, opaque containers at room temperature or below (preferably 15-25°C). Refrigeration (2-8°C) can extend shelf life but may not be necessary if other storage conditions are optimal.

Avoid exposure to direct sunlight, heat sources, and high humidity, which can accelerate degradation. For liquid formulations containing chalcones, store in airtight, opaque containers at room temperature or below (preferably 15-25°C). Refrigeration (2-8°C) can extend shelf life but may not be necessary if other storage conditions are optimal. Avoid exposure to direct sunlight and heat sources.

For enhanced delivery formulations, follow specific storage recommendations for each formulation. These may include refrigeration, protection from light, or other special considerations depending on the delivery system. After opening, all chalcone-containing products should be used within the recommended time frame specified by the manufacturer, typically 1-3 months for liquid formulations and 3-6 months for solid formulations. Proper sealing of containers after each use is important to minimize exposure to air and moisture.

For long-term storage of research-grade chalcones, aliquoting into smaller portions before freezing is recommended to minimize freeze-thaw cycles, which can accelerate degradation.

Exposure to oxygen – leads to oxidation, particularly at the α,β-unsaturated carbonyl group and hydroxyl groups, forming epoxides, diols, and other oxidation products, Exposure to UV light and sunlight – causes photodegradation, particularly isomerization of the trans-chalcone to the cis-chalcone, which is less stable, High temperatures (above 30°C) – accelerates decomposition and oxidation, Moisture – promotes hydrolysis of the carbonyl group and facilitates other degradation reactions, pH extremes – chalcones are most stable at slightly acidic to neutral pH (5-7), with increased degradation in strongly acidic or alkaline conditions, Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Nucleophilic compounds – can react with the α,β-unsaturated carbonyl group through Michael addition reactions, Enzymatic activity – certain enzymes, particularly oxidases and reductases, can degrade chalcones, Microbial contamination – can lead to enzymatic degradation of chalcones, Freeze-thaw cycles – can accelerate degradation, particularly in liquid formulations

Synthesis Methods

Natural Sources

Quality Considerations

Chalcones themselves were not identified or isolated as specific compounds until the late 19th and early 20th centuries, so their direct historical usage as isolated compounds is limited to recent scientific and medical applications. However, plants rich in chalcones have been used in traditional medicine systems for centuries, though their use was not specifically linked to chalcone content at the time. Licorice root (Glycyrrhiza glabra), one of the richest sources of chalcones such as isoliquiritigenin and licochalcone A, has a long history of medicinal use dating back to ancient civilizations. In traditional Chinese medicine (TCM), licorice root (known as ‘gan cao’) has been used for over 2,000 years as a harmonizing agent in many herbal formulations, as well as for treating coughs, reducing inflammation, and supporting digestive health.

The ancient Egyptians prepared licorice root tea as a healing drink, and it was found in the tomb of King Tutankhamun. In Ayurvedic medicine, licorice (known as ‘yashtimadhu’) was used to treat respiratory conditions, support adrenal function, and promote longevity. Greek and Roman physicians, including Hippocrates and Galen, prescribed licorice for respiratory ailments, digestive disorders, and as a general tonic. Citrus fruits and their peels, which contain naringenin chalcone and other chalcones, have been used in traditional medicine systems worldwide.

In TCM, dried citrus peel (known as ‘chen pi’) has been used for centuries to regulate qi, relieve cough, and improve digestion. In European folk medicine, citrus peels were used to treat digestive disorders, respiratory conditions, and as a general tonic. In the Americas, indigenous peoples used various citrus species for medicinal purposes after their introduction by European settlers. Turmeric (Curcuma longa), which contains curcumin (a compound with a chalcone-like structure in its enol form), has a long history of use in Ayurvedic and traditional Chinese medicine.

In Ayurveda, turmeric has been used for over 4,000 years for various conditions, including respiratory disorders, liver diseases, skin conditions, and wound healing. In TCM, turmeric (known as ‘jiang huang’) has been used to move blood, relieve pain, and treat various inflammatory conditions. Ashitaba (Angelica keiskei), a plant rich in chalcones such as xanthoangelol and 4-hydroxyderricin, has been used in traditional Japanese medicine, particularly in the Izu Islands and the Izu Peninsula. It was valued for its rejuvenating properties and was believed to promote longevity, improve digestion, and enhance overall health.

The name ‘ashitaba’ means ‘tomorrow’s leaf’ in Japanese, referring to the plant’s remarkable regenerative capacity, as a new leaf grows quickly after one is picked. Kava (Piper methysticum), which contains flavokawain A, flavokawain B, and other chalcones, has been used in traditional medicine in the South Pacific islands for centuries. It was used in ceremonial rituals and for its relaxing and anxiolytic properties. The scientific discovery and characterization of chalcones began in the late 19th century.

The basic chalcone structure was first synthesized by Kostanecki and Tambor in 1899 through the aldol condensation of acetophenone and benzaldehyde. The term ‘chalcone’ was derived from the Greek word ‘chalcos,’ meaning bronze, referring to the typical yellow-bronze color of many chalcones. Throughout the 20th century, research on chalcones expanded as analytical techniques improved, allowing for the isolation and characterization of these compounds from various plant sources. The Claisen-Schmidt condensation, a key method for chalcone synthesis, was developed and refined during this period.

In the latter half of the 20th century, research on chalcones shifted from structural characterization to biological activity. Studies began to elucidate the various biological properties of chalcones, including their antioxidant, anti-inflammatory, antimicrobial, and anticancer activities. This research was facilitated by advances in biochemical and molecular biology techniques that allowed for more detailed investigation of chalcones’ mechanisms of action. In recent decades, chalcones have attracted significant attention in medicinal chemistry and drug discovery.

Their relatively simple structure, combined with their diverse biological activities, makes them attractive scaffolds for the development of new therapeutic agents. Numerous synthetic chalcone derivatives have been developed and tested for various applications, including anticancer, anti-inflammatory, antimicrobial, and antidiabetic drugs. Today, while isolated chalcones are not typically available as consumer supplements, extracts of chalcone-rich plants such as licorice, citrus, and turmeric are used in various dietary supplements and functional foods. These modern applications represent a scientific evolution of the traditional uses of these plants, now informed by understanding of their chalcone content and the biological activities of these compounds.

Preclinical investigations into chalcones’ anticancer effects, particularly for hormone-dependent cancers such as breast, prostate, and ovarian cancer, Studies on chalcones’ anti-inflammatory effects and potential applications in inflammatory conditions such as arthritis, inflammatory bowel disease, and asthma, Investigations into chalcones’ antiviral effects, particularly against coronaviruses, influenza viruses, and HIV, Research on chalcones’ antidiabetic effects and potential applications in metabolic syndrome and obesity, Studies on chalcones’ neuroprotective effects and potential applications in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, Investigations into chalcones’ cardiovascular effects and potential applications in hypertension, atherosclerosis, and thrombosis, Research on the development of synthetic chalcone derivatives with enhanced bioavailability and therapeutic efficacy, Studies on the development of enhanced delivery systems for chalcones to improve their bioavailability and therapeutic efficacy, Investigations into the potential synergistic effects of chalcones with conventional drugs for various conditions, Limited clinical trials evaluating chalcone-containing plant extracts for various health conditions, including metabolic disorders, inflammatory conditions, and cancer prevention