Chalcone

Chalcone: A Comprehensive Reference

1. Identity: Chemical and Botanical Overview

Chalcone (systematic name: 1,3-diphenyl-2-propen-1-one, also written as 1,3-diaryl-2-propen-1-one or benzalacetophenone) is the parent compound of a large family of open-chain polyphenolic natural products. Chalcones are one of the major secondary metabolites of plants belonging to the flavonoid family. The scaffold of the chalcone (1,3-diphenyl-2-propene-1-one) contains two aryl rings (A and B), which are separated by α,β-unsaturated carbonyl groups. Chalcones exist in both cis and trans forms; the trans form is thermodynamically more stable.

Chalcones are secondary metabolites belonging to the flavonoid (C₆-C₃-C₆ system) family that are ubiquitous in edible and medicinal plants, and they are bioprecursors of plant flavonoids. A majority of naturally occurring chalcones are polyhydroxylated aromatic compounds, and they are considered the bioprecursors of open-chain flavonoids, flavonoids, and isoflavonoids. Chalcones' pharmacological properties are believed to result from a double bond conjugated to carbonyl functionality.

The term chalcone is derived from the Greek word chalcos, meaning bronze. Kostanecki together with Josef Tambor was the first who coined the term chalcone (Kostanecki and Tambor, 1899). The first chalcone described as a naturally occurring compound was carthamine, a natural red pigment from safflower (Carthamus tinctorius), a dye plant used in India; carthamine was used as a dye not only in ancient times but also later in the European wool-dyeing industry as well as in Japan for making cosmetics.

1.1 Structural Subclasses

The chalcone family can be roughly classified into two categories: simple and hybrid chalcones. They can further be classified into bichalcones, containing two chalcone moieties in one structure, or dihydrochalcones, with a reduced α,β-unsaturated double bond. Bichalcones, such as rhuschalcone from Rhus pyroides, contain two chalcone moieties in a single structure. Dihydrochalcones, such as the fleminchalcones from Flemingia philippinensis, are a class of compounds with a reduced α,β-unsaturated double bond.

The first dihydrochalcone, phlorizin (phloridzin), a naturally occurring flavonoid, was initially described by Philipp Lorentz Geiger in 1834; the German pharmacist and professor of pharmacy at the University of Heidelberg isolated it from apple root bark. When searching for how many chalcones are known, there is an overwhelming number of results, with at least 92,000 chalcones (including chalcone derivatives) being recorded, and more than 1,000 reporting biological activity.

1.2 Principal Natural Sources

Chalcones are polyphenolic compounds derived from plants and are abundant in edible plants like tomatoes, apples, licorice, and fingerroot. The majority of naturally occurring chalcones are polyhydroxylated aromatic compounds abundantly found in fruits, grains, legumes, vegetables, and beverages such as tea, coffee, red wine, and beer. The largest number of natural chalcones has been isolated from species of the Leguminosae, Asteraceae, and Moraceae families.

Notable source plants and their characteristic chalcones include:

• Licorice (Glycyrrhiza glabra, G. uralensis, G. inflata): About 42 chalcones have been isolated and identified from licorice. Key chalcones include isoliquiritigenin, licochalcones A, B, C, D, and E.
• Hops (Humulus lupulus): Xanthohumol (XN) is a prenylated chalcone flavonoid derived from hops (Humulus lupulus), best known as a bioactive component of hops and beer.
• Apples (Malus domestica): Phlorizin is a naturally occurring dihydrochalcone glycoside first isolated in 1835 as a bitter-taste substance from the root bark of an apple (Malus domestica Borkh.) tree.
• Cardamom and related Zingiberaceae species: Cardamonin is a hydroxychalcone isolated from a Zingiberous plant species, which possesses antimutagenic, vasorelaxant, and anti-inflammatory properties.
• Legumes including soy and shallots: Isoliquiritigenin (4,2′,4′-trihydroxychalcone) is found in various edible plants, including licorice (Glycyrrhiza glabra), soy beans (Glycine max), and shallots (Allium ascalonicum).

1.3 Common Forms and Preparations

Chalcones occurring in nature have plants as their major source. They are usually found either in medicinal plants or in dietary plants. In research and supplement contexts, chalcones are encountered in several forms:

• Standardized plant extracts: Most commonly derived from licorice root, hops, or apple. Licorice-derived chalcones appear in both oral and topical preparations.
• Isolated pure compounds: Individual chalcones such as xanthohumol, isoliquiritigenin, phloretin, and hesperidin methyl chalcone are available in purified or semi-purified supplement forms.
• Hesperidin methyl chalcone in pharmaceutical preparations: Hesperidin methyl chalcone has been tested and approved for the treatment of chronic venous lymphatic insufficiency.
• Micellar formulations: Recent advances in micellar formulations have improved xanthohumol's systemic bioavailability and thus its translational feasibility.
• Dietary intake: Chalcones are consumed as part of a normal diet via apples, licorice, hops-containing beverages, and various vegetables.

2. Traditional and Historical Use

Plants containing chalcones have been used in traditional medicines since antiquity. Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide.

2.1 Traditional Chinese Medicine

Licorice is an important Chinese materia medica frequently used in clinical practice. In traditional Chinese medicine (TCM), Glycyrrhiza glabra is considered an "essential herbal medication." According to a traditional Chinese medicine belief, "nine out of ten formulae contain licorice," and licorice is one of the most effective herbal medicines for reducing toxicity and increasing the efficacy of other herbal medicines when used together. The chalcones in licorice play a pivotal role when licorice exerts its pharmacological effects; licorice can be combined with various Chinese materia medica to form a variety of Chinese herbal compound prescriptions, such as Guizhi Gancao decoction, Shaoyao Gancao decoction, and Xuefu Zhuyu decoction.

Licorice has been used for centuries in traditional medicine as a life enhancer, for the treatment of coughs and influenza, and for detoxification. Licorice has been used to treat inflammatory diseases since ancient times in China. Licorice has also been documented to help with fatigue and debilitation in China, and acts as an anti-inflammatory, reducing allergic responses and preventing liver damage.

2.2 Ayurvedic and South Asian Traditions

Licorice has a long history of use in traditional Chinese, Ayurvedic, and herbal medicine. Chalcone-bearing plants such as licorice have been documented in Ayurvedic practice under the Sanskrit name Yastimadhu. Plants' therapeutic properties have been recorded in Egyptian civilizations, Chinese medicine, Indian Ayurveda, and on Assyrian clay tablets dated around 2000 B.C.

2.3 Ancient Egyptian, Greco-Roman, and Near Eastern Traditions

The chalcone carthamine, a natural red pigment from safflower (Carthamus tinctorius), was used as a dye not only in ancient times but also later in the European wool-dyeing industry as well as in Japan for making cosmetics. According to the World Health Organization, licorice (a major chalcone-containing plant) is used as a demulcent for sore throats and an expectorant for bronchial catarrh and coughs.

2.4 Traditional Preparations

Chalcone-containing plants have historically been prepared as aqueous decoctions, infusions, and powders for internal use, as well as topical applications in pastes and poultices. Plants comprising chalcones have been utilized in traditional medicine for decades. Licorice is not only a bulk medicine for traditional Chinese medicine but also a major raw material for Mongolian medicine and an important component of many folk prescriptions. The therapeutic applications of chalcones have been associated since time immemorial for the treatment of different diseases.

3. Biosynthesis in Plants

Flavonoids are synthesized via the phenylpropanoid and polyketide pathway, which starts with the condensation of one molecule of CoA-ester of cinnamic acid or derivatives such as coumaric or ferulic acid, and three molecules of malonyl-CoA, yielding a naringenin chalcone as major product. This reaction is carried out by the enzyme chalcone synthase (CHS). The chalcone is then isomerized to a flavanone by the enzyme chalcone flavanone isomerase (CHI). From these central intermediates, the pathway diverges into several branches, each resulting in a different class of flavonoids.

Chalcone synthase is the first committed enzyme of the flavonoid biosynthetic pathway and catalyzes the production of 2′,4,4′,6′-tetrahydroxychalcone (THC). Chalcone synthases (CHSs) are plant-specific polyketide synthases that appear to be ubiquitous in higher plants. They utilize CoA-esters from the phenylpropanoid pathway and malonyl-CoA to synthesize the chalcones that are the starting material for the biosynthesis of a large number of biologically important substances; their roles include flower colors, UV protection, defense against pathogens (phytoalexins), interaction with microorganisms, and fertility.

The flavonoid biosynthesis occurs through the phenylpropanoid pathway, starting with phenylalanine. Key enzymatic steps include the transformation of phenylalanine into trans-cinnamic acid by phenylalanine ammonia-lyase (PAL), followed by its transformation into 4-coumaric acid and then into 4-coumaroyl-CoA. Chalcone synthase then catalyzes the condensation of 4-coumaroyl-CoA with malonyl-CoA to produce chalcone, which can be further modified into various flavonoid subclasses.

4. Key Constituents and Active Compounds

The chalcone family encompasses hundreds of distinct naturally occurring members. Some examples of bioactive chalcone compounds known for their biological activities include phloretin, butein, isoliquiritigenin, licochalcone E, xanthohumol, and chalconaringenin. Chalconaringenin, phloretin, and its glucoside phloridzin (phloretin 2′-O-glucose) are some of the most common chalcones present in food.

4.1 Xanthohumol

Xanthohumol (XN) is a prenylated chalcone flavonoid derived from hops (Humulus lupulus), best known as a bioactive component of hops and beer. In recent years, XN has attracted broad research interest because it modulates multiple disease-relevant pathways involving inflammation, oxidative stress, metabolism, and cell survival. As potential antitumor-promoting mechanisms, xanthohumol has demonstrated anti-inflammatory properties by inhibition of COX-1 and COX-2 activity as well as inhibition of the NLRP3 inflammasome and NF-κB signaling pathway activation, but has also been shown to prevent carcinogenesis in the progression phase, which includes inhibition of DNA synthesis and induction of cell cycle arrest in the S-phase, apoptosis, and cell differentiation.

4.2 Isoliquiritigenin

Isoliquiritigenin (4,2′,4′-trihydroxychalcone) is found in various edible plants, including licorice (Glycyrrhiza glabra), soy beans (Glycine max), and shallots (Allium ascalonicum), and has been found to possess anti-inflammatory activity and to exhibit significant cytotoxic and anticancer activities such as induction of cell cycle arrest and induction of apoptosis in human gastric cancer cells. This anti-inflammatory effect has been shown to be associated with an induction of antioxidant and detoxification enzymes, including UGT, NQO1, and HO-1. Isoliquiritigenin (2',4',4-trihydroxychalcone, ISL) extracted from licorice root has a chalcone structure that exhibits a strong anticancer effect.

4.3 Phloretin and Phlorizin

Phloretin, which is found in the apple plant, has weak antidiabetic properties but displays a range of pharmacological effects including antibacterial, anticancer, and cellular and organ protective properties both in vitro and in vivo. Being a chalcone compound and having unsaturation and phenolic hydroxyl moieties, phloretin has shown the potential to modify various protein functions, leading to reversal of abnormal signaling and cellular transformation. The isolation of phlorizin from the bark of an apple tree in 1835 led to a flurry of research on its inhibitory effect on glucose transporters in the intestine and kidney. Using phlorizin as a prototype drug, antidiabetic agents with more selective inhibitory activity towards glucose transport at the kidney have subsequently been developed.

4.4 Licochalcones

Among the licorice chalcones, licochalcone A (LCA), licochalcone B (LCB), licochalcone C (LCC), licochalcone D (LCD), and licochalcone E (LCE), as well as isoliquiritigenin (ISL), have all been reported to possess anti-inflammatory activity. Glycyrrhizin, its metabolite glycyrrhetic (glycyrrhetinic) acid, and other liquorice-derived compounds such as isoflavonoids and trans-chalcones exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade, and α_2A-adrenoceptor antagonism.

4.5 Cardamonin

Cardamonin (CD) has been shown to modulate a variety of signaling molecules involved in the development and progression of neurodegenerative disease, including transcription factors (NF-κB and STAT3), cytokines (TNF-α, IL-1, and IL-6), enzymes (COX-2, MMP-9, and ALDH1), and other proteins and genes (Bcl-2, XIAP, and cyclin D1).

5. Established Mechanisms of Action

5.1 Antioxidant Activity

Due to the presence of phenolic groups, chalcones have a radical quenching property, which has created interest among researchers to investigate chalcone-rich plant extracts in search for therapeutically useful compounds. The medicinal benefits of polyhydroxylated chalcones are mainly attributed to their free radical scavenging activity (antioxidant property), which in turn mitigates oxidative stress-induced tissue damage associated with some chronic disorders such as cardiovascular diseases and inflammation. The pharmacological properties of chalcones are assumed to be due to the existence of a double bond in conjugation with the carbonyl moiety, as steric hindrance or saturation of the double bond renders the activity significantly reduced.

5.2 Anti-inflammatory Mechanisms

Chalcones are widely utilized for their diverse biological functions, including antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, and renoprotective effects. Key anti-inflammatory mechanisms include:

• NF-κB pathway inhibition: Natural and synthetic derivatives of chalcones can modulate the NF-κB and STAT3 signaling pathways, the excessive activation of which plays an essential role during the carcinogenesis of various types of cells.
• COX enzyme inhibition: Chalcones, found in plants such as Glycyrrhiza, Piper, Angelica, and Ruscus, show activity comparable to that of COX-2 enzyme inhibition and a moderate effect against COX-1.
• NLRP3 inflammasome suppression: Isoliquiritigenin alleviates early brain injury in rats after intracerebral hemorrhage induction via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by triggering the Nrf2 antioxidant system.
• Nrf2 pathway induction: Xanthohumol has been shown to induce HO-1 and NQO1 via the Keap1-Nrf2-ARE regulatory pathway, which may account for some of the anti-inflammatory and chemopreventive effects of this compound.

5.3 Anticancer Mechanisms

Studies have shown that chalcones can inhibit the growth and proliferation of cancer cells, induce apoptosis, and suppress tumor angiogenesis. Specific mechanistic actions include:

• Apoptosis induction: Isoliquiritigenin suppresses Epithelial-Mesenchymal Transition (EMT) markers like vimentin and N-cadherin and induces apoptosis by modulating Bax, Bim, and Fas and downregulating Bcl-2.
• NF-κB DNA binding suppression: In pancreatic cancer cells (PANC-1), xanthohumol decreased the binding to DNA in both subunits of NF-κB p50 and NF-κB p65.
• Chemosensitization: An in vitro model showed increased sensitivity to chemotherapy as a result of the synergistic effect of chemotherapy with butein, phloretin, isoliquiritigenin, xanthohumol, and isoxanthohumol.
• Radiosensitization: An increase in the sensitivity of stomach, lung, and breast cancer cells to radiotherapy was observed after the use of butein, phloretin, and xanthohumol, respectively.

5.4 Antidiabetic Mechanisms

Novel naturally occurring chalcones are recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. Several synthetic chalcones have been reported to have potential inhibitory activity against α-glucosidase or α-amylase. The antidiabetic potential of chalcone derivatives has been demonstrated through their ability to mitigate insulin resistance and β-cell dysfunction in diabetic rats.

5.5 Antimicrobial Mechanisms

Natural chalcones have an intense antimicrobial activity that targets many pathogens, including viruses, bacteria, fungi, and protozoa. Strong antibiotic qualities are exhibited by chalcones including 4-hydroxyderricin, licochalcone A and C, isobavachalcone, and pinocembrin chalcone. Flavonoid compounds such as chalcones inhibit the growth of bacteria by acting on the membrane potential, which might affect the overall bacterial metabolic activity, resulting in some biosynthetic pathway inhibition, as demonstrated by the strong inhibition of DNA, RNA, and protein synthesis.

6. Scientific Evidence by Area of Use

6.1 Chronic Venous Insufficiency (Human Clinical Evidence)

Clinical trials have revealed chalcone use in the treatment of chronic venous insufficiency. Chronic venous insufficiency (CVI) is a clinical syndrome that results from chronic disorders of venous circulation from the lower limb level. The main symptoms in moderate stages are heavy legs, tension in the lower limbs, varicose veins dilated, followed in severe stages by swelling of the lower limbs, skin changes, and the appearance of venous ulcer.

From the clinical point of view, a significant and lasting reduction of the symptoms was obtained in patients treated with the mixture of chalcone and vitamin C compared to the group treated only with rutozide (Beltramino et al., 1999). Study results concerning symptoms like pain, cramps, heaviness, and swelling show some variation; however, micronised purified flavonoid fractions (MPFF) and ruscus extract combined with hesperidin methyl chalcone and ascorbic acid demonstrated the highest quality of evidence, primarily at level A. Hesperidin methyl chalcone has been tested and approved for the treatment of chronic venous lymphatic insufficiency.

Evidence strength: Level A evidence exists specifically for hesperidin methyl chalcone in combination with other venoactive agents for CVI; this represents the strongest body of clinical evidence for any single chalcone-class compound in human medicine.

6.2 Anticancer Activity (Predominantly Preclinical)

Recent in vitro and in vivo research suggests tremendous therapeutic potential for natural and synthetic chalcone derivatives as compounds in multiple combinations and nanoformulations demonstrating better anticancer effects. Chalcones are a type of natural flavonoid compound that have been found to possess promising anticancer properties; studies have shown that chalcones can inhibit the growth and proliferation of cancer cells, induce apoptosis, and suppress tumor angiogenesis. In addition to their potential therapeutic applications, chalcones have also been studied for their chemopreventive effects, which involve reducing the risk of cancer development in healthy individuals.

Epidemiological and experimental evidence indicates that xanthohumol is able to prevent proliferation and migration, rendering this agent a useful chemopreventive cancer agent. XN was found to exert anti-proliferative effects in human breast cancer MCF7 cells and in prostate epithelial cells. As a chemopreventive agent in vivo, isoliquiritigenin has been shown to prevent, for example, colon cancer in a mice carcinogenesis model.

Clinical trials have revealed chalcone use in the treatment of cancer. However, the body of human clinical trial evidence specifically for isolated chalcones in cancer treatment remains limited, and the majority of evidence derives from in vitro cell line studies and animal models. The low bioavailability of chalcones encourages the design of new synthetic derivatives whose modified structure would increase possibilities for use in the therapy or prevention of cancer.

Evidence strength: Predominantly in vitro and in vivo (animal); human clinical data are early-stage and insufficient to establish efficacy claims. The chalcone xanthohumol is currently undergoing clinical investigation.

6.3 Anti-inflammatory Activity (Preclinical and Early Clinical)

Preclinical studies on chalcones and their derivatives have shown their high potential as anti-inflammatory agents. The anti-inflammatory properties of phloretin include inhibiting the signaling pathways of inflammatory mediators' expression that support its suppressive effect in immune cells overactivation, obesity-induced inflammation, arthritis, endothelial, myocardial, hepatic, renal, and lung injury, and inflammation in the gut, skin, and nervous system, among others.

Some other activities have also been reported for chalcones as a class: anti-spasmodic, tranquilizing, analgesic, sedative, anti-thrombic, vasodilatory, estrogenic, anesthetic, anti-coagulating, anti-convulsant, and diuretic activities.

Evidence strength: Robust preclinical data; human trial data are limited and not sufficient to establish specific dosing or efficacy in inflammatory conditions without further randomized controlled trials.

6.4 Antidiabetic Potential (Preclinical; Derivative-Driven Drug Development)

The isolation of phlorizin from the bark of an apple tree in 1835 led to a flurry of research on its inhibitory effect on glucose transporters in the intestine and kidney. Using phlorizin as a prototype drug, antidiabetic agents with more selective inhibitory activity towards glucose transport at the kidney have subsequently been developed. This gave rise to the SGLT2-inhibitor drug class (gliflozins), representing a major pharmaceutical advance directly rooted in chalcone chemistry.

Several synthetic chalcones have been reported to have potential inhibitory activity against α-glucosidase or α-amylase. The IC₅₀ value of synthetic intermediate chalcones varied between 15 ± 0.14 and 385 ± 5.60 μM. Tris-chalcone derivatives all showed higher inhibition profiles than those of acarbose.

Evidence strength: The most clinically validated pharmacological application arising from chalcone chemistry is the development of SGLT2 inhibitors derived from phlorizin. For naturally occurring chalcones as direct antidiabetic supplements, human clinical evidence is preliminary.

6.5 Antimicrobial and Antiparasitic Activity (Preclinical)

Chalcones are basically α,β-unsaturated ketones that exert great diversity in pharmacological activities such as antioxidant, anticancer, antimicrobial, antiviral, antitubercular, antiplasmodial, antileishmanial, immunosuppressive, and anti-inflammatory activities. Chalcone-accumulating plants have often been used in traditional medicine, and chalcones have therefore been studied and reported to possess many beneficial biological effects including anti-inflammatory, antimicrobial, antifungal, antioxidant, cytotoxic, antitumor, and chemopreventive activities.

Some of the chalcones have been implicated in inhibition of exoenzymes responsible for fungal invasion mechanisms, also inhibiting biofilm and germ tube formation as in Candida albicans. They may affect the cellular cytoplasmic membrane and induce cell apoptosis.

Evidence strength: Primarily in vitro; minimal controlled clinical data. The antimicrobial activity of individual chalcones in human trials has not been robustly established.

6.6 Neuroprotection (Preclinical)

Preclinical studies on chalcones and their derivatives have shown their high potential as neuroprotective agents. Cardamonin has received particular attention for neuroprotective properties, with research into Alzheimer's disease applications. Cardamonin has been shown to modulate a variety of signaling molecules involved in the development and progression of neurodegenerative disease, including transcription factors (NF-κB and STAT3), cytokines (TNF-α, IL-1, and IL-6), and enzymes (COX-2 and MMP-9).

Evidence strength: All evidence is preclinical (cell lines and animal models). No established human clinical evidence for neuroprotection.

6.7 Skin Conditions (Early Clinical Evidence)

Clinical trials have revealed chalcone use in the treatment of skin conditions. Licochalcone A, derived from licorice, has been investigated in topical formulations for its anti-inflammatory and antimicrobial effects in skin disease, including acne and atopic dermatitis, though the clinical evidence base remains limited. XN is a safe, multifunctional natural compound with strong potential for modulating disease-relevant biological pathways associated with inflammatory skin conditions.

Evidence strength: Some clinical signals, particularly for hesperidin methyl chalcone and licochalcone A in topical preparations; larger randomized trials are needed.

6.8 Cardiovascular Health (Preclinical)

Experimental studies show a variety of cardioprotective effects for xanthohumol, but so far there are only a few controlled studies on the bioavailability and efficacy of xanthohumol in humans. Isoliquiritigenin improves kidney function by reducing urea and urinary creatinine levels, increasing glomerular filtration rate, improving creatinine clearance, and reducing ROS/RNS and MDA levels to protect against oxidative stress, while also increasing GSH and SOD activity.

Evidence strength: Preclinical only for most cardiovascular endpoints. The xanthohumol human bioavailability randomized controlled trial (described below) addresses this gap partially.

7. Bioavailability and Pharmacokinetics

Bioavailability studies on chalcones and derivatives indicate possible hindrance and improvement in relation to their nutraceutical and pharmaceutical applications. Intestinal absorption and consequently the bioavailability of many flavonoids are limited due to their hydrophobic properties. Only a limited amount of data from animal models and human studies is available on the bioavailability of xanthohumol. These data indicate that xanthohumol is poorly absorbed and rapidly metabolized and excreted, which limits its bioavailability.

Metabolism of xanthohumol is characterized by its rapid isomerization to isoxanthohumol, which presumably occurs mostly in the gastrointestinal tract. Xanthohumol has been reported to be a substrate of P-glycoprotein (P-gp) and multi-drug resistance protein (MRP2) and found to have low oral bioavailability (8.676%) with the colon as the best absorption site.

In a human randomized crossover bioavailability trial: plasma kinetics of 86 mg and 172 mg each of micellar or native xanthohumol were investigated. Blood samples were obtained at fasting, regularly until 9 hours and 24 hours after oral xanthohumol bolus administration. Micellation increased the area under the plasma concentration–time curve (AUC) (p < 0.001) and maximum plasma concentration (p < 0.001). This suggests that formulation engineering can meaningfully improve chalcone bioavailability.

New nano-formulations are being explored in order to increase bioavailability, prolonged effect, or transport to the target of the action for chalcones.

8. Dosage Forms and Reported Dosages

There is no universally established recommended daily intake for chalcones as a supplement class. Reported doses across studies and clinical contexts vary substantially by individual compound and formulation. The following dosages are reported as they appear in referenced sources only:

• Xanthohumol (human bioavailability study): In a randomized crossover bioavailability trial, plasma kinetics of 86 mg and 172 mg each of micellar or native xanthohumol were investigated.
• Synthetic chalcones (antidiabetic enzyme inhibition studies): The IC₅₀ values of synthetic intermediate chalcones varied between 15 ± 0.14 and 385 ± 5.60 μM in enzyme inhibition studies. These are in vitro values and do not translate directly to human dosing.
• Hesperidin methyl chalcone: This compound has been approved and used clinically in Europe for chronic venous insufficiency in pharmaceutical preparations, though specific dosing from independently sourced clinical protocols is not reported in the reviewed literature in quantitative detail.

Clinical studies on chalcones revealed general absence of adverse effects besides reducing the clinical signs and symptoms with decent bioavailability. Further studies are needed to elucidate their structure–activity relationships, toxicity concerns, cellular basis of mode of action, and interactions with other molecules.

9. Body Systems and Health Areas

Based on the available evidence, chalcones and their derivatives have been associated with the following body systems and health areas:

• Cardiovascular and venous system: Hesperidin methyl chalcone for CVI; preclinical data for cardioprotection.
• Immune and inflammatory system: NF-κB, NLRP3, and STAT3 modulation; COX inhibition.
• Oncology: Preclinical anticancer, pro-apoptotic, anti-angiogenic, and chemopreventive activity; early clinical investigation.
• Endocrine/metabolic system: Antidiabetic α-glucosidase and GLUT-4 mechanisms; SGLT inhibition prototype (phlorizin).
• Nervous system: Neuroprotective and antioxidant mechanisms (preclinical only).
• Skin and integumentary system: Topical anti-inflammatory and antimicrobial applications.
• Respiratory system: Historically used (as licorice preparations) for cough and bronchial conditions.
• Gastrointestinal system: Antimicrobial activity; licorice preparations historically for ulcer and digestive complaints.
• Renal system: Renoprotective effects demonstrated preclinically with isoliquiritigenin.
• Hepatic system: Emerging evidence suggests licorice-derived natural products (including chalcones) relieve liver diseases and prevent drug-induced liver injury through multi-targeting therapeutic mechanisms, including anti-steatosis, anti-oxidative stress, anti-inflammation, immunoregulation, anti-fibrosis, and anti-cancer.

10. Safety Considerations and Drug Interactions

Chalcones have been extensively studied for their bioactivities, which are associated with low toxicity. Clinical studies on chalcones revealed general absence of adverse effects besides reducing clinical signs and symptoms with decent bioavailability. Further studies are needed to elucidate their structure–activity, toxicity concerns, cellular basis of mode of action, and interactions with other molecules.

10.1 Drug Interactions: CYP3A4 and P-glycoprotein

Naturally occurring chalcones have been found to affect the pharmacokinetic parameters of drugs when administered simultaneously. Oral administration of nifedipine with licochalcone A has been found to inhibit CYP3A4 as well as exhibit the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp, leading to a higher peak plasma concentration. This suggests that chalcones capable of inhibiting CYP3A4 could theoretically alter plasma concentrations of co-administered drugs metabolized by this enzyme.

It has been proposed that the co-administration of chalcone-containing botanical extracts (Boesenbergia rotunda) with therapeutic drugs may cause herb–drug interactions, leading to an alteration of the efficacy and toxicity of the drug.

10.2 P-glycoprotein Substrate Status

Xanthohumol has been reported to be a substrate of P-glycoprotein (P-gp) and multi-drug resistance protein (MRP2). This is relevant in the context of co-administration with drugs also transported by these efflux pumps, including certain chemotherapeutic agents, immunosuppressants, and antivirals.

10.3 Isoliquiritigenin and Hormonal Effects

Research has raised questions regarding isoliquiritigenin's potential to interfere with sex hormone biosynthesis, an important consideration for populations with hormone-sensitive conditions or individuals using hormone therapies.

10.4 Licorice-Specific Toxicity Context

There have been no reports of potentially toxic compounds from the taxa studied so far. However, some adverse consequences are recognized, such as using high dosages over a prolonged period, resulting in serious illnesses. These known risks pertain primarily to glycyrrhizin-containing licorice preparations (pseudoaldosteronism, hypertension, hypokalemia) rather than to isolated chalcone fractions specifically, though the distinction is important in evaluating whole-plant preparations.

10.5 Gaps in Toxicological Knowledge

Although chalcones have shown many interesting biological effects and many preclinical experiments could be performed, their mechanism of action is not entirely known. Being compounds that could be synthesized relatively easily, it is necessary to develop new synthesis methods that allow the research of new biological properties, a deeper knowledge of the molecular mechanisms of action, and especially the identification of the targets of action. Further research and clinical trials can explore their pharmacological actions, their interactions with other compounds or medicines, and the level of toxicity they can cause.

11. Current Research Landscape and Future Directions

Scientists have been fascinated by chalcones, the building blocks of several pharmacologically intriguing metabolites extracted from natural sources, for decades. Researchers are still fascinated by the chemistry of chalcones in the 21st century, owing to their easy preparation and several replaceable hydrogens that generate an extensive range of derivatives and intriguing biological functions.

In view of having tremendous pharmacological potential, chalcone scaffolds/chalcone derivatives and bioflavonoids after subtle chemical modification could serve as a reliable platform for natural products-based drug discovery toward promising drug lead molecules/drug candidates. Xanthohumol is currently undergoing clinical trials for its potential chemopreventive activity.

XN is a safe, multifunctional natural compound with strong potential for modulating disease-relevant biological pathways associated with cancer, neurodegenerative diseases, metabolic disorders, and inflammatory skin conditions. Continued efforts to enhance its bioavailability and conduct rigorous clinical trials are essential to fully establish its clinical relevance in patient populations.

Natural and synthetic derivatives of chalcones can modulate the NF-κB and STAT3 signaling pathways, the excessive activation of which plays an essential role during the carcinogenesis of various types of cells. Recent in vitro and in vivo research suggests tremendous therapeutic potential for natural and synthetic chalcone derivatives as compounds in multiple combinations and nanoformulations demonstrating better anticancer effects.

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