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Pharmacological Properties of Chalcones: A Review of Preclinical Including Molecular Mechanisms and Clinical Evidence

Bahare Salehi, Cristina Quispe, Imane Chamkhi and 14 more

Frontiers in Pharmacology · 2021 · Review · CC BY

doi:10.3389/fphar.2020.592654

Abstract

Chalcones are among the leading bioactive flavonoids with a therapeutic potential implicated to an array of bioactivities investigated by a series of preclinical and clinical studies. In this article, different scientific databases were searched to retrieve studies depicting the biological activities of chalcones and their derivatives. This review comprehensively describes preclinical studies on chalcones and their derivatives describing their immense significance as antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive, and neuroprotective agents. Besides, clinical trials revealed their use in the treatment of chronic venous insufficiency, skin conditions, and cancer. Bioavailability studies on chalcones and derivatives indicate possible hindrance and improvement in relation to its nutraceutical and pharmaceutical applications. Multifaceted and complex underlying mechanisms of chalcone actions demonstrated their ability to modulate a number of cancer cell lines, to inhibit a number of pathological microorganisms and parasites, and to control a number of signaling molecules and cascades related to disease modification. 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, toxicity concerns, cellular basis of mode of action, and interactions with other molecules.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Chalcones are among the leading categories of flavonoids across the entire kingdom of plant. The term chalcone is originated from the Greek name chalcos which means bronze. Chalcones were initially manufactured in the research lab in late 1800s. The chalcone chemistry has created thorough scientific research all the way through the globe.

Naturally existing chalcones were not separated till the year 1910. Chalcones that derived from nature exist mostly as colors of petal and furthermore have been established in the heartwood, leaf, bark, fruit, and root of a range of plants and botanicals.

Chalcones are also recognized as benzyl acetophenone. Chalcones are alpha, beta unsaturated ketones holding two fragrant rings (rings A and B) having different arrangement of substituents. In chalcones, two fragrant rings are connected by an aliphatic three carbon series (Figure 1).

Plants containing chalcones, for instance, the Glycyrrhiza, Piper, Angelica, and Ruscus genus, have long been utilized as therapeutic remedies in Balkan countries. Numerous unadulterated chalcones were accepted for clinical applications or experimented in humans. Licochalcones segregated from the plant of licorice has been stated to have a range of biological activities, for instance, antispasmodic, chemopreventive, antimalarial, antitumour, anti-inflammatory, antifungal, antioxidant, and antibacterial activities. Both apples and sour fruits are loaded nutritional sources of dihydrochalcones and chalcones. Moreover, these complexes could even compose a better contribution to the overall daily consumption of unrefined or organic polyphenolics compounds than other considerably researched flavonoids.

The purpose of this review is to summarize the most important pharmacological activities highlighting the cellular and molecular mechanisms of action of natural and synthetic chalcones, to better understand their therapeutic potential in the future.

Search Strategy

An extensive research was conducted into the available scientific databases PubMed, Scopus, Scielo, and Science Direct using the terms “chalcones,” “bioavailability,” “biological activities,” “anti-inflammatory,” “antidiabetic,” “neuroprotective,” “antioxidant,” “anticancer,” “antibacterial,” and “antifungal.”

Inclusion Criteria

The inclusion criteria included research studies or reviews that reported the pharmacological actions of chalcones were included; articles published in English, book chapters that also included phytochemical data, and preclinical studies on cell cultures or animal model with evidence of cellular and molecular mechanisms of action; studies that included chalcones and their derivatives from plants whose nomenclature is included in the Plant List (http://www.theplantlist.org/).

Exclusion Criteria

The exclusion criteria included abstracts, case reports, and conference proceedings that did not meet the inclusion criteria, as well as studies that included homeopathic preparations.

Data Collection

Selected pharmacological studies included data on chalcones and their derivatives analyzed, experimental model (in vivo or in vitro), dose, concentration, and results of pharmacological activities with molecular mechanisms included. All information obtained and analyzed in this comprehensive and updated review were summarized in tables and figures.

Preclinical Pharmacological Activities of Chalcones

Preclinical studies on chalcones and their derivatives have shown their high potential as antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive, and neuroprotective agents (Figure 2).

In Vitro Antidiabetic Activity

Several synthetic chalcones have been reported to have potential inhibitory activity against α-glucosidase or α-amylase.

The IC50 value of synthetic intermediate chalcones (1–24) varied between 15 ± 0.14 and 385 ± 5.60 μM. Similar observations were noted with the Chana series, and with the tris-chalcone derivatives (5a-5i), all showing higher inhibition profiles than those of acarbose. Studies on hydroxyl chalcones and bis-chalcones (1a-1m) and (2a-2m) were performed in connection to the inhibition kinetics. By using the abovementioned methods, natural chalcone derivatives (morusalbins A-D) showed significant inhibitory activities against α-glucosidase. 3ʹ,5ʹ-digeranylated chalcone (16) demonstrated noncompetitive inhibition characteristics. In another study, compound 4m was found to be the most active compared to the other chalcone-triazole derivatives. Numerous studies have shown some chalcones and/or their derivatives (such as chalcone 1 with an IC50 of 840 ± 2.50 μM while that of acarbose was 860.23 ± 6.10 μM) with significant inhibitory effects than those of the standards used.

Chalcone units of conjugates also exhibited moderate inhibitory activities against α-glucosidase, with the highest activity (IC50 = 3.2 ± 0.2 µM) recorded by conjugate 1b. Moreover, moderate inhibitory effect was observed by piperonal chalcones derivatives against α-amylase.

Four chalcone derivatives were synthesized, and it was found that the compound 3-(4-hydroxyphenyl)-1-phenylprop-2-en-1-one has an inhibitory effect on α-amylase. Chalcone 4 (butein) has been shown to be the most potent compound among 41 derivatives, exhibiting significant inhibition of α-glucosidase, moderate inhibition of α-amylase, and competitive inhibition of both the enzymes.

In another study, chalcone 20 was the most active inhibitor (IC50 = 0.4 µM) of α-glucosidase among 20 derivatives, exhibiting noncompetitive inhibition. In addition, the inhibitory capacity of chalcones 1–13 and bis-chalcones 14–18 against α-amylase (IC50 = 1.25 ± 1.05–2.40 ± 0.09 µM) was found to be comparable to that of acarbose (IC50 = 1.04 ± 0.3 µM). Furthermore, researchers have recorded promising activities of different chalcones in inhibiting the aforementioned enzymes, occupying the active sites.

A study evaluated the antidiabetic activity of sulfonamide chalcone derivatives in silico using methods like homology modeled structure, molecular docking, and MD simulation. This study indicated that these derivatives can bind to residues of the active site as the same way as drugs such as acarbose and voglibose.

Prenylated chalcones (3, 4, 7) and flavanone-coupled chalcones (9, 12, 13) of Boesenbergia rotunda (L.) Mansf. roots exhibited inhibition greater than 90% at the concentration of 20 μg/ml plus an inhibitory power of α-glucosidase higher than that of acarbose (IC50 = 1.2 mM). A natural chalcone (lavandulylated chalcone) exhibited inhibitory activity against β-glucosidase (IC50 = 57 μM) while noncompetitively inhibiting α-glucosidase. Similarly, another study isolated xanthohumol (XN) from Humulus lupulus L. as a potential inhibitor of α-glucosidase (IC50 = 8.8 μM) reversibly and noncompetitively. Other natural chalcones (6, 7, 20) were identified by from Derris indica (Lam.) Bennet root extract as a moderate inhibitor of α-glucosidase, and compound 6 showed the most potent activity (IC50 = 103.5 µM).

Natural prenylchalconaringenins (1) and (2) have been investigated for their inhibitory properties against digestive enzymes; 3′-geranylchalconaringenin (2) showed moderate inhibition of α-amylase (IC50 = 20.46 µM) and competitive and irreversible inhibition of α-glucosidase (IC50 = 1.08 µM). In addition, these two enzymes were also inhibited by three natural chalcones from Psoralea corylifolia. Another chalcone (2ʹ,4ʹ-dihydroxy-6ʹ-methoxy-3ʹ,5ʹ-dimethylchalcone) (DMC) from Cleistocalyx operculatus (Roxb.) Merr. and L.M.Perry flower buds inhibited pancreatic α-amylase (IC50 = 69.35). Regarding GLUT4-dependent glucose uptake, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), two natural chalcones from Angelica keiskei (Miq.) Koidz. stem juice, increased this uptake via the signaling pathway of LKB1/AMP-activated protein kinase in 3T3-L1 adipocytes.

In Vivo Antidiabetic Activity

Several authors have evaluated the antihyperglycemic activity of synthetic chalcones in streptozotocin-induced diabetic rats. It was found that these compounds have a moderate to potential ability to reduce blood sugar. The same effect was noted in starch-loaded rats, using chalcone derivative 8c. Moreover, serum glucose levels were measured in hyperglycemic rats treated with chalcone analogs, which showed a significant antihyperglycemic effect.

In a study conducted by Damazio et al., it was evaluated the antihyperglycemic activity of nitrochalcones and naphthylchalcones in diabetic rats by determining blood glucose levels, insulin secretion, and 14C-glucose uptake into the soleus muscle of the animal. This indicates that the effect of chalcones on lowering blood glucose in the hyperglycemic rat can be attributed mainly to insulin secretion with potency similar to that of glipizide. In addition, the glycogen levels in the liver, brain, and spinal cord of rats were estimated following 25 mg/kg dose of chalcone administration for 7 days to discover that these chalcones were able to reduce the glycogen content in the liver, and therefore exerted a strong antidiabetic activity. Furthermore, when 2-hydroxychalcone was administered to male rats, they rendered insulin resistance by a high fructose diet. This chalcone was found to have significant hypoglycemic activity by increasing insulin secretion and glycosylated hemoglobin.

Chalcone derivatives (4A-4E) were tested on sucrose-loaded diabetic albino mice to find that compound 4-C (2-(3-(4-methoxyphenyl)-1H-pyrazol-5-yl) phenol) achieved the most promising activity, which is supported by docking study. For male mice (type 2 diabetes), at doses of 200–300 mg/kg/day, 2′, 4′-dihydroxy-4-methoxydihydrochalcone (DMC-2) exhibited a hypoglycemic effect comparable to that of metformin (antidiabetic drug).

Chalcone derivatives (13a-h) and (19a-h) instreptozotocin-induced diabetic mice, compounds13e, 13g, and 19f reduced TG, TC, and Glu levels, respectively. Diabetic mice were treated with trihydroxychalcone derivatives, and therefore, chalcone 13 stimulated activation of AMP-activated protein kinase (AMPK), increased muscle FAO, improved tolerance to glucose, and decreased fat accumulation in the liver and skeletal muscles. Hypoglycemic activity of sulfonylurea chalcones 1-3 was also exhibited in normoglycemic rabbits to show that all these chalcones have activity comparable to that of gliclazide.

Significant hypoglycemic effects were displayed by five isoliquiritigenin (ISL) derivatives isolated from Glycyrrhiza glabra L. rhizomes tested in streptozotocin-induced diabetic mice, chalcone-6ʹ-hydroxy-2ʹ,3,4-trimethoxy-4ʹ-O-β-D-glucopyranoside (1) from Pouzolzia rugulosa (Wedd.) Acharya & Kravtsova. leaves tested in alloxan-induced diabetic mice, and 2′4-dihydroxy chalcone-4-glucoside from Adhatoda zeylanica Medik. flower. Likewise, in mice with hyperglycemia, xanthoangelol (XA) and 4-hydroxyderricin (4HD), two major types of chalcones derived from Angelica keiskei (Miq.) Koidz. lowered blood sugar by demonstrating insulin-like activity with preventive effects of (4HD) on the development of diabetes in genetically diabetic KK-Ay mice.

Table 1 summarizes the in vitro and in vivo antidiabetic properties of natural and synthetic chalcones.

Anti-Inflammatory Activity

Literature reported several chalcones and their derivative that have shown promise to inhibit cyclooxygenase (COX) (Table 2). In a study to assess the anti-inflammatory effect, new chalcone derivatives using carrageenan-induced hind paw edema model, the results showed that 5′-chloro-2′-hydroxy- 4′6′-dimethyl-3, 4, 5-trimethoxychalcone (1) exhibited the most potent anti-inflammatory activity with a 90% inhibition of edema. In another study, a novel class indole-based chalcones were evaluated for their inhibitory effects on COX-1 and COX-2, and showed remarkable inhibition of COX-1. The nitrogen-containing chalcone derivatives showed inhibition of some enzymes implicated to inflammatory process such as β-glucuronidase, COX-2, and trypsin. In another investigation, the synthetic fluoro-hydroxy substituted pyrazole chalcones demonstrated that exhibited selective inhibitory effect against COX-2 enzyme and a moderate effect against COX-1. The activity was related to the inhibition of COX-2.

Natural chalcones have also shown their ability to inhibit COX-1 and COX-2: 2-hydroxy-3,4,6-trimethoxychalcone isolated from Toussaintia orientalis Verdc. root and stem bark extracts had a potent inhibitory effect against both the enzymes.

Chalcones exhibited promising activity against NO and PGE2 (Table 2). The effect of dimethylamino-chalcones on the generation of NO and PGE2 mediators was studied in LPS-stimulated RAW 264.7 macrophage cells. The results showed that chalcones suppressed NO production in a dose-depending manner. In another study, in order to evaluate the inhibitory effects of trimethoxychalcone derivatives on NO production, the results showed a suppression of NO and PGE2 in LPS-activated RAW 264.7 macrophage cells by 2,4,6-trimethoxy-20-trifluoromethylchalcone. This suggestion was supported by the data which showed an inhibition of nitrite and PGE2 levels.

Natural chalcones have also shown the ability to inhibit NO and PGE2 production. Mallotophilippen chalcones isolated from Mallotus philippinensis fruit extracts, exhibited suppression of NO synthesis in a murine macrophage-like cell line. Xanthohumol and dihydroxanthohumol isolated from Humulus lupulus L. are other natural chalcones, which considerably inhibited NO production by suppressing iNOS induced by LPS and INF-γ in a murine macrophage-like cell line.

Chalcones also have proved their ability to inhibit NF-κB. Other chalcone derivatives such as isoliquiritigenin, butein, and homobutein have suppressed TNF-α mediated by the inhibition of NF-κB gene expression. Isoliquiritigenin also reduced palmitic acid–induced macrophage activation, leading to additional anti-inflammatory activity. In human primary endothelial cells Isoliquiritigenin prevented the translocation and stimulation of NF-κB by hindering the phosphorylation and subsequent decomposition of IkBα.

Antimicrobial and Antifungal Activity

From the leaves and stems of Crotalaria madurensis Wight & Arn., crotmadine (1) was isolated that exhibited antifungal activity. Five prenylated flavonoids, including one new natural product (2–6), were isolated from an ethanol extract of the leaves of Maclura tinctoria (L.) D. Don ex Steud. All the isolated compounds were evaluated against Candida albicans and Cryptococcus neoformans. Compound 3 (isobavachalcone) was found to be the most active against both the yeasts (ElSohly et al., 2001). The crude methanolic extract of Zuccagnia angulata Hook. and Arn. by assay guided fractionation led to the isolation of two chalcones (7–8) as the compounds responsible for the antifungal activity. The antifungal activity of the chalcones (9–13), extracted from the methanol extract of the leaves of Artocarpus nobilis Thwaites, showed potent fungicidal activity. A new dimeric chalcone (14) isolated from the fresh whole uncrushed fruits of Mallotus philippinensis var. pallidus Airy Shaw was evaluated for antifungal susceptibility with good results. The extracted compounds from Zuccagnia punctata Cav. were found to be efficacious as inhibitors of Candida species. In a recent study, the antifungal activity of 40 synthetized chalcones and analogs (20–59) was analyzed. Chalcones with different substituents showed to be active against different tested fungi probably by inhibiting the biosynthesis of one or both polymers of the fungal cell wall. A large series of chalcones were synthesized and studied for antifungal activity against Candida albicans; the chalcones (60–64) exhibited promising anti-candidal activities.

As part of ongoing studies in developing new antimicrobials, ten new thiazole-based chalcones (77–86) were synthesized and tested for their in vitro antifungal properties. These possessed modest activity against all the fungal species tested and were being less active than ketoconazole and bifonazole. The chromonyl chalcones (87–88) were used as intermediates for the synthesis of new bioactive pyrazoline derivatives (89–94) under green condition. The antifungal and antimicrobial activity was tested by disk diffusion assay. The maximum inhibition was observed by chalcones 84 and 89 against S. aureus. Using the agar cup-plate method, the antimicrobial activities of the synthesized compounds (95–106) were screened in vitro. The results exhibited promising antifungal activity and antibacterial activity. Compound 107 was evaluated for its antibacterial properties and showed maximum zone of inhibition against S. aureus and P. aeruginosa. A series of a-triazolyl chalcones were synthesized (108–121), and the synthesized compounds showed potent antibacterial activity and antifungal activity. A new series of pyrazine analogs of chalcones have been tested against fungal strains. The results showed that the compounds were inactive or only weekly active against most strains. In another study, a series (132–179) of isatin–ferrocenyl chalcone and isatin–ferrocene conjugates were synthesized and were evaluated for their inhibitory activities against T. vaginalis. The compounds exhibited 100% growth inhibition. In another study, three chalcones, diuvaretin, uvaretin, and isouvaretin, were investigated on their antibacterial activity, and the culture inhibition was only observed for Gram-positive germs. A series of ten chalcones and five new dihydrochromane–chalcone hybrids (189–203) were synthesized, and their antifungal activity was evaluated in vitro, and only two compounds had similar antifungal activity to that of the positive control. A series of five fluorinated chalcones (204–208) were evaluated for their antibacterial activity against Gram-positive and Gram-negative pathogenic bacterial strains using the agar diffusion method. The results showed that the compounds exhibited broad-spectrum activity against these pathogens.

Antileishmanial Activity

The in vitro antileishmanial activity of chalcones was evaluated by several studies.

Licochalcone inhibited the growth of both Leishmania major and Leishmania donovani promastigotes and amastigotes and reduced the infection rate of human peripheral blood monocyte-derived macrophages. Adunchalcone displayed 50% effective concentrations against the promastigote forms of Leishmania (L.) amazonensis, L (V.) braziliensis, L (V.) shawi, and L (L.) chagasi, respectively. In another study, chalcones obtained Psorothamnus polydenius (S.Watson) Rydb., and exhibited leishmanicidal properties. The chalcone 2,6′-Dihydroxy-4'-methoxychalcone (DMC) showed significant activity against promastigotes and intracellular amastigotes of Leishmania amazonensis. Many other chalcone-derived plants displayed varying degrees of leishmanicidal activity such as isoliquiritigenin, chalcone from Lonchocarpus xuul Lundell, chalcones from Calea uniflora Less (family Compositae), and sulfonamide 4-methoxychalcone derivatives. A series of oxygenated chalcones demonstrated remarkable antileishmanial activity. The compound derived from triclosan was evaluated for antileishmanial activity against L (V) panamensis amastigotes, and the compound was found to be active against Leishmania parasites. The compounds of methoxychalcones and another synthetic chalcone, 2',4′-dihydroxychalcone displayed potent in vitro antileishmanial activity. Also, chalcones (1–4) displayed potent leishmanicidal activity via reducing the infection index of macrophages significantly (De Mello et al., 2014).

In vivo, licochalcone A has completely prevented lesion development in L. major–infected mice. Chromenochalcones also showed antileishmanial potential in hamster. Oral administration of chalcone 3-nitro-2-hydroxi-4,6-dimetoxychalcone (CH8) in the groups of animals infected with either Leishmania infantum or Leishmania amazonensis showed good effect.

Table 3 summarizes the antileishmanial effects of chalcones using in vitro and in vivo approaches.

Antimalarial Activity

Naturally occurring chalcones have demonstrated promising potencies after being tested in vitro against Plasmodium falciparum. The compounds bartericin A, stipulin 3, 4, and hydroxylonchocarpin demonstrated particular antimalarial potential with relatively low doses. Other chalcones with antimalarial activity proved in vitro: cajachalcone, xanthohumol, sulfonamide chalcone derivatives, sythesized novel chlorovinyl sulfone-like chalcone derivatives, quinolinyl chalcones synthesized (Domínguez et al., 2001), various 1,3-diaryl-2-propenones (chalcone derivatives), and chalcone chloroquinolines such as chloroquine and quinine. Among the 27 novel chalcone derivatives synthesized, only one compound was found to be the most antimalarial active.

Chalcone derivatives administrated intraperitoneally to the Plasmodium yoelii–infected mice model showed significant inhibition of these strains.

Table 4 summarizes the principal studies carried out on the antimalarial effect of natural and synthetic chalcones.

Cytotoxic and Antiproliferative Activity

Chalcones (natural and derivatives) displayed potent antiproliferative consequences in both initial as well as developed ovarian cell carcinoma and also in stomach carcinoma HGC-27 cell (Table 5).

Chalcones with piperazine moiety have demonstrated different, as well as, crucial pharmacological activities counting antihistamine, antioxidant, anti-inflammatory, anti-infective, and anticarcinogenic properties. In the light of piperazine moiety, biological activity has also been reported and encouraged.

Chalcones with piperazine moiety were created, and their in vitro anti-carcinoma–producing activity was observed. New fragrant chalcones with in vitro anti-carcinoma–producing property have also been recorded. In addition, Jurkat cell line of human T-lymphocyte blood cancer along with HL-60 human blood cancer cell lines is also targeted by diaryl chalcones. The in vitro study was performed for ascertaining compound activity in opposition to two breast carcinoma cell lines MCF-7 and T47D. Table 6 The result specified that all the compounds were dynamic but not analogous with doxorubicin. However, it displayed some effects against two breast carcinoma cell lines. In another study, 25 chalcone-derived compounds were reported to exhibit anticarcinogenic properties. Recent research conducted on 46 different chalcones to measure exact antiproliferative activities against the human tumor necrosis factor–associated programmed cell death–inducing ligand (TRAIL) against cervical (HeLa), liver (HepG2), breast (MCF-7, MDA-MB-231), ovarian (Caov-3), nasopharyngeal (CNE-1), erythromyeloblastoid (K-562), lung (A549), colorectal (HT-29), T-lymphoblastoid carcinoma cells (CEM-SS), and common human embryonic kidney (HEK-293) cells.

Chalcone derivatives with enone and thiophene rings also possess activity against tubulin assembly and colchicines; they bind to tubulin of K562 cells (chronic myeloid leukemia; CML) and inhibit their growth on G2/M stage of the cell cycle. In addition, those thiophene chalcone derivatives inhibit human T-lymphocyte (Molt 4 and CEM) and human cervix cancer (HeLa) cells. This research was conducted on murine blood carcinoma (L1210), murine mammary cancer (FM3A), human HeLa, Molt 4, and CEM cells by taking 0.3–0.5 million cells/mL of culture medium. After incubating the cells with testing compounds at 37°C for 2 days, cell number was counted by means of a Coulter counter.

Anticancer Potential of Chalcones

Cancer is one of the most feared diseases of the 21st century—according to the 2012 Globocan report, 14 million people are diagnosed with cancer each year and more than 8 million deaths are reported each year. Because radiotherapy or chemotherapy has multiple adverse effects, new molecular therapies are being tested for use in the treatment of solid tumors and blood cancers. Targeted molecular therapy uses the patient’s genetic information to determine which molecules can act most effectively in concerning to the type of diagnosed cancer. Thus, heat-shock proteins 90 (HSP90) inhibitors open new perspectives in cancer treatment by destabilizing proteins by which cancer cells survive and multiply (tumorgenesis). Recent studies from last years have shown that synthetic chalcones can have a HSP90 inhibitory effect. Several phase II clinical trials of new anticancer molecules that have two hydroxyl groups at positions 1,3 revealed inhibition of interactions between HSP90 and patients' proteins through binding of these molecules to the ATP site in HSP90. Maybe in the future, phase III clinical trials will be conducted to support the anticancer potential of chalcones and their derivatives.

Neuroprotective Activity

A research has been conducted on 10 different chalcones, out of which two have nearly similar activity as of diazepam: isoliquiritigenin (ISL, 2’,4’,4-trihydroxychalcone) and butein (BUT, 2’,4’,3,4,tetrahydroxychalcone). This research based on outcomes of chalcones on different replacements, investigated in animal models for instance open field experiment, equine protozoal myeloencephalitis test, rotarod performance, and grip analysis. These experiments are typical models for screening CNS actions giving information regarding tranquilizing or sleep inducing, psychomotor performance, anxiety, and muscle-relaxant effects. The kinetic study of ISL to monoamine oxidase-A indicated that it merged to variable positions of the enzyme, independent of the pre-binding of serotonin. In the wide-ranging perception, reasonably lipophilic medicines traverse the blood–brain barrier (BBB) by submissive diffusion. Opposing molecules are usually poor central nervous system agents, except they pass through dynamic transport across the central nervous system. Hence, it can be approximated that they are able to traverse the BBB and attain their target. Chalcones one, nine, fourteen, fifteen, and sixteen with fine affinity for the BZD binding positions of the GABA category A receptors, chalcones one and five with attraction for the 5-hydroxytryptamine1A receptor, and compounds six and twelve for the µ-opioid receptor were preferred to be experimented as antidepressants, anti-anxiety agents, and against the sensation and perception of pain in extensively applied pharmacological experiments in rats. During the tail suspension experiment, chalcone one demonstrated antidepressant-like activity in rodents, while compound six demonstrated action against sensations and perceptions of pain in an acute chemical stimulated nociception assessment.

The new fifty-methyl-twenty-hydroxy-thirty-nitrochalcone exhibited marginal and central activities against perceptions and sensations of pain either in acute thermal or chemical nociception experiments. According to the consequences recapitulated, plain chalcone derived compounds are favorable compounds for the discovery and growth of new central nervous system medicines and contain an encouraging scaffold in medical chemistry for the evolution of medicines and for the management of pain, depression, and anxiety.

Chalcones in 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. A therapeutic option is represented by laser therapy, sclerotherapy, and venoactive drugs. These venoactive drugs are a heterogeneous group of substances from plant or synthetic origin that modulate the venous tone, attenuates the blood rheology, improves micro- and macrocirculation, regulates capillary permeability, have anti-inflammatory effects by inhibiting leukocyte–endothelial interaction, and reduces the oxidative stress.

Recent clinical trials have shown the main role of two chalcones hesperidin methylchalcone and hesperidin trimethylchalcone in the treatment of chronic venous disorders and varices of the trunk of the internal saphenous vein, respectively. In a randomized open-label study, the therapeutic effect of a mixture of hesperidin methyl chalcone, Ruscus aculeatus with vitamin C compared to rutozide in patients diagnosed with chronic venous insufficiency was investigated. This clinical trial was conducted for three months and included eighty patients divided into two groups: the first group received the combination with hesperidin methyl chalcone, and the second received only rutoside. The signs and symptoms of chronic venous insufficiency were evaluated initially and then monthly. From the clinical point of view, a significant and lasting reduction of the symptoms was obtained in the patients from the first group treated with the mixture of chalcone and vitamin C compared to the second group, treated only with rutozide.

The mechanism of the venotonic effect of Ruscus and hesperidin methylchalcone extract is exerted by a two-way adrenergic mechanism: 1) direct effect as agonist of the postjunctional alpha-adrenergic receptors of the smooth cell in the vascular wall and 2) indirect effect expressed by increasing the release of noradrenaline from the presynaptic vesicles. The dose–effect relationship in the single dose and the respective role of each constituent of this combination with hesperidin methylchalcone (150 mg), Ruscus aculeatus plant (150 mg per capsule), and ascorbic acid (100 mg) on the venous tone were also demonstrated in a clinical study that included 37 women with superficial venous insufficiency. It has been shown that the effect of a capsule administered twice daily is similar to the administration of two capsules daily in the morning, and no adverse digestive effects have been reported. Clinical efficiency consisted in improving the permeability of the vascular walls, increasing the vascular tone, reducing the edema and normalizing the blood circulation in the blood vessels. Similar beneficial effect of hesperidin methylchalcone (HMC) on lymphatic venous insufficiency in a recent meta-analysis of some clinical trials has also been demonstrated. The good tolerability and the reduced adverse effects of the combination of HMC, Ruscus extract, and vitamin C have led the specialists to propose their inclusion in the new treatment guidelines for chronic venous insufficiency.

In a randomized double-blind study, the pharmacological effect of trimethyl hesperidine chalcone associated with Ruscus extract and vitamin C was demonstrated in patients diagnosed with femoral trunk varicose. The study included fifty patients, divided into two groups: one orally treated 14 days with this combination and the other with placebo. In both the groups, the venous tone was evaluated by plethysmography, both in motion and at rest. In the group treated with trimethyl hesperidine chalcone associated with Ruscus extract and vitamin C, the clinical signs were significantly reduced.

Chalcones in Treatment of Skin Conditions

Skin diseases are leading causes of morbidity with high prevalence and incidence, affecting the patients’quality of life and being associated with very important social, economic, and healthcare costs. This is why the search for new treatment options in dermatology is one of the most important research areas in both fundamental and clinical science.

Various clinical trials have evaluated the role of chalcones in inflammatory skin conditions and one of the most investigated substances was licochalcone A. An interesting study including sixty-two women with persistent mild to moderate facial redness has evaluated skin compatibility and effect of a skin care regimen containing licochalcone A with duration of 8 weeks. The topical products were very well tolerated, and the results of the study showed significant improvements of erythema and in quality of life of the patients. A subsequent study on 33 rosacea patients showed that the skin care products with licochalcone A are compatible with the standard topical treatment of the disease.

Another research has assessed the effects on sensitive skin of licochalcone A in combination with 4-t-butylcyclohexanol. The authors have conducted a single-blind, randomized study in order to evaluate subjective and objective symptoms of skin sensitivity. The formulation containing licochalcone A-rich licorice extract combined with 4-t-butylcyclohexanol showed a significant reduction of shaving-induced erythema. It was suggested that the anti-inflammatory effect of licochalcone A is induced by a significant reduction of NFκB signaling and prostaglandin E2 (PGE2) secretion.

A recent randomized, prospective, investigator-blinded study has evaluated the effects of a moisturizer containing 4-t-butylcyclohexanol and licochalcone A on eighty patients with mild to moderate facial dermatitis. The chalcone containing topical treatment has induced significant improvements of clinical aspect, hydration of cutaneous tissue, and transepidermal water loss as well as the patients' subjective evaluation. The results of facial moisturizer were compared with those induced by 0.02% triamcinolone acetonide cream and even if the topical corticoid treatment was associated with faster improvement of patients’ symptoms, the chalcone containing moisturizer showed better effects on skin hydration and inflammation control.

A complex research including two clinical studies and several in vitro experiments was conducted in order to evaluate the anti-irritative effect of cosmetic formulations containing licochalcone A. The prospective randomized vehicle-controlled clinical trials enrolled a total of 57 healthy subjects, 45 of them being included in study using a post-shaving skin irritation model and 12 volunteers taking part in a UV-induced erythema test. Even if in one model inflammation was induced by impairment of skin barrier and in the second by UV-penetration damage, in both studies, the topically applied licochalcone A-rich licorice extract showed a highly anti-irritative effect, significantly reducing erythema. The additional in vitro data emphasized possible cellular and molecular mechanisms showing a strong inhibitory effect of licochalcone A on pro-inflammatory responses of different cell types such as granulocytes, keratinocytes, dermal fibroblasts, and monocyte-derived dendritic cells.

Moreover, licochalcone A has proved to be effective in scalp disorders. The effect of a tonic solution containing licochalcone A, among other active components, has been investigated in 30 subjects with dry and itchy scalp conditions and showed a significant reduction of scalp dryness, itching, and microinflammation. The role of chalcones in the treatment of inflammatory skin conditions in children is another important area of research. A randomized, double-blind, split-side comparison study on 75 infants between the age of 2 weeks and 1 year showed that a moisturizer containing 0.025% licochalcone is equally effective as topical 1% hydrocortisone for the treatment of infantile seborrhoeic dermatitis. The same research group, in a multicenter randomized, prospective, split-side, double-blind study, has evaluated the effect of a moisturizer containing licochalcone A compared to 1% hydrocortisone topical therapy in the treatment of childhood atopic dermatitis. The study included 55 children with mild to moderate lesions and showed that the moisturizer containing licochalcone A significantly reduces the clinical severity of the lesions and the transepidermal water loss, being equally effective as topical corticosteroid treatment. Moreover, continuing the treatment with licochalcone A moisturizer was able to stabilize the clinical improvement and the skin barrier recovery. These results are in accordance with data from a previous randomized, controlled, investigator-blinded study.

Chalcones are also evaluated as potential treatment options in acne patients. A double-blinded, prospective, randomized, vehicle-controlled clinical trial has investigated the tolerability and effect of a moisturizer containing licochalcone A, l-carnitine, and 1,2-decanediol as adjuvant treatment in topical therapy with retinoids. The study included 120 subjects with mild to moderate acne and showed a significant reduction of total lesions in patients treated with the moisturizer containing active substances. Moreover, they had less inflammatory lesions and skin irritations.

Anti-aging medicine is another important area of research in which chalcones are investigated. A double-blind, placebo-controlled trial including ninety-two subjects showed that oral intake of Boesenbergia pandurata extract containing panduratin A as bioactive compound for 12 weeks significantly increases skin hydration and gloss and decreases wrinkling without any adverse symptoms, suggesting a possible use of Boesenbergia pandurata extract as a nutraceutical or nutricosmetic product.

Bioavailability of Chalcones

Research on the bioaccessibility of chalcones from sources of food are bounded, but experimented artificial chalcones have accounted to contain broad ranges of biological activities. Although chalcones have an essential position in the bio-production of flavonoids and are familiar in a number of foods and drinks, like rooibos tea or apples, there are unavailability of data on their bioaccessibility in human beings.

The prenylated chalcone xanthohumol is the amplest chalcone produced in hop cones. Throughout beer preparation, a huge fraction of xanthohumol is changed to the related isomeric prenylflavanone isoxanthohumol. Following administration of xanthohumol to rodents by force feeding at extremely elevated dosage (1 g/kg of body weight), linked metabolites were identified in plasma. The most important metabolite, xanthohumol- 49-O-glucuronide, attained its topmost concentration of 3.1 lmol/L 4 h after administration. The maximum concentration of unmetabolized xanthohumol was 10 times lower with the similar Tmax of 4 h. One more rodent study discovered only conjugates in plasma following oral administration of xanthohumol however unsuccessful to distinguish unmetabolized xanthohumol.

Conversely, these studies demonstrate that prenylated chalcones are bioavailable, although their bioaccessibility appears to be commonly low.

Another study explored the prospective accessibility of flavanones in diversely processed Citrus sinensis (L.) Osbeck juices by imitating stomach and small intestinal in vitro digestion.

In addition to showing the power of pasteurization and storage on the substance of dissolvable flavanones, these researchers detected that in vitro pancreatin intake of Citrus sinensis (L.) Osbeck juice in a mild alkaline medium, imitating absorption in the small intestine, converted fifty to sixty% of the dissolved flavanones (primarily hesperidin) to chalcones (principally hesperidin chalcone). Particularly the poor dissolvability of a large number of chalcone compounds, the bioequivalence effectiveness has not achieved the anticipated intensities in preclinical assessments.

Therefore, the maximization of the physicochemical activities will be one of the principal study routes of chalcone-dependent compounds. For the objects of chalcone compounds, a number of anticipated targets must be confirmed. Activity-dependent protein outlining is a potent approach for recognition of target that must be decided by considering each case individually because of the properties of chalcone molecules.

Discussion

The results of our study confirmed the therapeutic potential of chalcones. The limitations of this research result from the fact that many meta-analyzes were included and not individual studies. But this can be considered as a strong point because recent meta-analyzes have summarized the most important pharmacological effects in vitro and especially in vivo. Another strength of this review is that the latest studies and clinical trials on patients have been described, thus confirming the clinical importance and positive prospects in medical therapy.

Natural and synthetic chalcones and their derivatives presented antidiabetic effects, and the effect can be attributed mainly to lowering of insulin secretion with potency similar to that of hypoglycemic agents (ig Glipizide). Numerous studies have reported the anti-inflammatory effects of chalcones on several targets such as enzymes implication in promoting inflammation process: cyclo-oxygenase, interleukins, nitric oxide synthase, cell adhesion molecules (CAM), lipo-oxygenase (LOX), and prostaglandins (PGs). The suppression and/or inhibition of cyclo-oxygenase enzyme is a promising therapeutic way in the treatment of inflammatory diseases. Many bioactive compounds, both natural and synthetic, have been isolated and synthetized to develop anti-cyclooxygenase activity. PGE2 and NO are among the inflammatory mediators that promote inflammation in several diseases. Consequently, the inhibition of these mediators is strongly suggested as remedy for numerous inflammatory diseases.. Chalcones also have proved their ability to inhibit NF-κB (nuclear factor kappa) which regulates the most important factors involved in inflammatory process such as cytokines, chemokines, and adhesion molecules. Several studies have suggested the use of chalcones and their derivatives target specifically NF-κB as an anti-inflammatory therapeutic strategy.

Chalcones are natural products, produced by plants as a natural defense mechanism against pathogens as fungi and bacteria. Synthesized β-chlorovinyl chalcones exhibited antifungal activity. In general, the natural chalcones (synthesized or modified) are being increasingly documented because of their interesting antimicrobial activities and can be represented as promising agents in the perspective of new antibiotic drugs discovery. 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 C. albicans. They may affect the cellular cytoplasmic membrane and induce cell apoptosis as it was noted in case of carvacrol. In addition, it was also reported that flavonoid compounds 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. Chalcones also showed to be a promising anticancer potential because it induces selective cell death in carcinoma cells with not upsetting regular cells and psychoactive and neuroprotective activities. (Brady et al., 2012).

Overall Conclusions and Future Perspectives

The curiosity and attraction toward natural compounds are increasing gradually because of the recognized favorable consequences on numerous prevalent and general diseases like carcinoma, allergic reactions, cardiovascular disease, infectious diseases, parasitic diseases, type 2 diabetes mellitus, or diseases of central nervous system. Starting from the ethnopharmacological uses of chalcones, in this study, the most important in vitro and in vivo biological activities such as antibacterial, antioxidant, antineoplastic, cytotoxic, antiulcer, antidepressant, anxiolytic, and anti-inflammatory were highlighted. Chalcones derivatives have shown anticancer activity against a variety of cancer cell lines, antibacterial activity against Gram-negative and Gram-positive germs, and anti protozoal activity. Although conducted in a small number, clinical studies of chalcones have shown a lack of adverse effects in patients with chronic venous insufficiency, the reduction of clinical signs and symptoms, and good plasma concentrations. However, further clinical studies are needed to fully understand the mechanisms of action at the cellular level and to establish correlations between their structure and pharmacological actions, especially anticancer activity.

Although they showed 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, in the future, 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 target of the action. And so, this successful story of the promising therapeutic effects of chalcones to be applicable in the discovery of new drugs, pharmaceutical forms, using modern strategies, especially new nano-formulations in order to increase their bioavailability, prolonged effect, or transport to the target of the action. Further research and clinical trials can explore its pharmacological actions, their interactions with other compounds or medicines, and the level of toxicity it can cause.

Author Contributions

JS-R, MM, and DC: conceptualization. BS, IC, NE, ABa, ABo, MA, and MI: validation investigation. CQ, JS-R, CC, AD, and MM: resources. CQ, JS-R, CC, GL-G, AD, MM, and FL: data curation. JS-R, AD, MM, DC, VL, and FL: review and editing. All authors: writing. All authors read and approved the final version, and contributed equally to the manuscript.

Funding

This research and article processing charges were funded by a grant of Romanian Ministry of Research and Innovation, CCCDI-UEFISCDI project number 61PCCDI/2018 PN-III-P1-1.2-PCCDI-2017-0341, within PNCDI-III.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Ferlay J. Soerjomataram I. Ervik M. Dikshit R. Eser S. Mathers C. Rebelo M. Parkin D. M. Forman D. Bray F. (2013 ). GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer. Available at: http://globocan.iarc.fr.

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    Imran S. Taha M. Ismail N. H. Kashif S. M. Rahim F. Jamil W. (2015 ). Synthesis of novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR analysis and docking studies. Eur. J. Med. Chem. 105, 156–170.

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    Jayanthi M. Jegatheesan K. Vidhya R. Kanagavalli U. (2012 ). Hypoglycemic effect of 2-hydroxychalcone on high fructose fed diabetic rat. Int. J. Pharm. Sci. Res. 3, 600.

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    Jeong C.-H. Park H. B. Jang W. J. Jung S. H. Seo Y. H. (2014 ). Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC). Bioorg. Med. Chem. Lett. 24, 224–227.

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    Kumar S. Sharma A. Madan B. Singhal V. Ghosh B. (2007 ). Isoliquiritigenin inhibits IκB kinase activity and ROS generation to block TNF-α induced expression of cell adhesion molecules on human endothelial cells. Biochem. Pharmacol. 73, 1602–1612.

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    Liu M. Yin H. Liu G. Dong J. Qian Z. Miao J. (2014 ). Xanthohumol, a prenylated chalcone from beer hops, acts as an α-glucosidase inhibitor in vitro. J. Agric. Food Chem. 62, 5548–5554.

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    Maccari R. Ottanà R. (2015 ). Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions. J. Med. Chem. 58, 2047–2067.

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    Mahapatra D. K. Bharti S. K. Asati V. (2017a ). Chalcone derivatives: anti-inflammatory potential and molecular targets perspectives. Curr. Top. Med. Chem. 17, 3146–3169.

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    Mititelu R. R. Pădureanu R. Băcănoiu M. Pădureanu V. Docea A. O. Calina D. (2020 ). Inflammatory and oxidative stress markers—mirror tools in rheumatoid arthritis. Biomedicines 8, 125

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    Polyphenolic Content, Antioxidant and Antimicrobial Activities of Lycium barbarum L. and Lycium chinense Mill. Leaves · 2014
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    Monisha E. Suganya V. Anuradha V. Syed Ali M. (2018 ). Antioxidant, anti-inflammatory and antidiabetic activity of some novel chalcone and piperidine derivatives. Int. Res. J. Pharmacy Med. Sci. 2, 2581–3277.

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    Moosavi M. A. Haghi A. Rahmati M. Taniguchi H. Mocan A. Echeverría J. (2018 ). Phytochemicals as potent modulators of autophagy for cancer therapy. Cancer Lett. 424, 46–69.

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    Mounika K. L. S. (2015 ). Silico evaluation of alpha glucosidase and alpha amylase, inhibitory activity of chemical constituents from psoralea corylifolia. Int. J. Chem. Res. 8, 532–538.

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    Naidu M. A. Prasad Y. R. (2018 ). Evaluation of antidiabetic activity of novel diarylsulfonylureachalcone hybrids in streptozotocin-induced diabetic models in rats. Asian J. Pharm. 12, S382‐S405.

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    Najafian M. Ebrahim-Habibi A. Yaghmaei P. Parivar K. Larijani B. (2010 ). Core structure of flavonoids precursor as an antihyperglycemic and antihyperlipidemic agent: an in vivo study in rats. Acta Biochim. Pol. 57, 553–560.

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    Ngameni B. Watchueng J. Boyom F. F. Keumedjio F. Ngadjui B. T. Gut J. (2007 ). Antimalarial prenylated chalcones from the twigs of dorstenia barteri var. subtriangularis. Arkivoc 13, 116–123.

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    Nowakowska Z. (2007 ). A review of anti-infective and anti-inflammatory chalcones. Eur. J. Med. Chem. 42, 125–137.

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    Nyandoro S. Nkunya M. Josepha C. Odalo J. Sattler I. (2012 ). New glucopyranosylglyceryl-N-octenyl adipate and bioactivity of retro and condensed chalcones from Toussaintia orientalis. Tanzan. J. Sci. 38, 108–126.

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    Oh Y. J. Seo Y. H. (2017 ). A novel chalcone-based molecule, BDP inhibits MDA-MB-231 triple-negative breast cancer cell growth by suppressing Hsp90 function. Oncol. Rep. 38, 2343–2350.

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    Ohta M. Fujinami A. Kobayashi N. Amano A. Ishigami A. Tokuda H. (2015 ). Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes. Nutr. Res. 35, 618–625.

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  124. 124.
    Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity. · 2017
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  125. 125.

    Orlikova B. Schnekenburger M. Zloh M. Golais F. Diederich M. Tasdemir D. (2012 ). Natural chalcones as dual inhibitors of HDACs and NF-κB. Oncol. Rep. 28, 797–805.

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    Otero E. Vergara S. Robledo S. M. Cardona W. Carda M. Vélez I. D. (2014 ). Synthesis, leishmanicidal and cytotoxic activity of triclosan-chalcone, triclosan-chromone and triclosan-coumarin hybrids. Molecules 19, 13251–13266.

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    Özdemir A. Altıntop M. D. Turan-Zitouni G. Çiftçi G. A. Ertorun I. Alataş Ö. (2015 ). Synthesis and evaluation of new indole-based chalcones as potential antiinflammatory agents. Eur. J. Med. Chem. 89, 304–309.

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    Peralta G. A. Gardoqui J. A. Macías F. L. Ceja V. N. Cisneros S. M. Macías C. M. (2007 ). Clinical and capillaroscopic evaluation in the treatment of chronic venous insufficiency with Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid in venous insufficiency treatment of ambulatory patients. Int. Angiol. 26, 378.

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    Prasath R. Bhavana P. Ng S. W. Tiekink E. R. (2013 ). The facile and efficient ultrasound-assisted synthesis of new quinoline-appended ferrocenyl chalcones and their properties. J. Organomet. Chem. 726, 62–70.

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    Purnima S. Beena P. Mini R. Swaminathan P. (2012 ). Study of the effect of Adhatoda zeylanica and some related synthesized chalcones on glucose diffusion in vitro. ARPB 2, 259–263.

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    Rahaman S. Prasad Y. R. Bhuvaneswari K. Kumar P. (2010 ). Synthesis and antihistaminic activity of novel pyrazoline derivatives. Int. J. Chem. Tech. Res. 2, 16–20.

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    Raju D. B. Rao A. V. Prasad Y. R. (2018 ). Hybrid sulfonylurea-linked chalconoids as antidiabetic agents: evaluation of antihyperglycemic effects in streptozotocin-induced type 2 diabetic rats. Rasayan J. Chem. 11, 1334–1338.

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    Rao M. V. Rao A. V. Mujavar E. (2014 ). Evaluation of the in vivo hypoglycemic effect of sulfonylurea-chalcone hybrid molecules in normoglycemic rabbits. J. Global Trends Pharm. Sci. 5, 1797–1803.

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    Rawat P. Kumar M. Rahuja N. Srivastava D. S. L. Srivastava A. K. Maurya R. (2011 ). Synthesis and antihyperglycemic activity of phenolic C-glycosides. Bioorg. Med. Chem. Lett 21, 228–233.

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    Ribnicky D. M. Kuhn P. Poulev A. Logendra S. Zuberi A. Cefalu W. T. (2009 ). Improved absorption and bioactivity of active compounds from an anti-diabetic extract of artemisia dracunculus L. Int. J. Pharm. 370, 87–92.

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    Rocha S. Sousa A. Ribeiro D. Correia C. M. Silva V. L. Santos C. M. (2019 ). A study towards drug discovery for the management of type 2 diabetes mellitus through inhibition of the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase by chalcone derivatives. Food Funct. 10, 5510–5520.

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    Rojas J. DomíNguez J. N. Charris J. E. Lobo G. Payá M. Ferrándiz M. L. (2002 ). Synthesis and inhibitory activity of dimethylamino-chalcone derivatives on the induction of nitric oxide synthase. Eur. J. Med. Chem. 37, 699–705.

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    Rojas J. Payá M. Devesa I. Dominguez J. N. Ferrándiz M. L. (2003a ). Therapeutic administration of 3, 4, 5-trimethoxy-4'-fluorochalcone, a selective inhibitor of iNOS expression, attenuates the development of adjuvant-induced arthritis in rats. Naunyn Schmiedebergs Arch. Pharmacol. 368, 225–233.

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    Rojas J. Payá M. DomíNguez J. N. Ferrándiz M. L. (2003b ). ttCH, a selective inhibitor of inducible nitric oxide synthase expression with antiarthritic properties. Eur. J. Pharmacol. 465, 183–189.

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    Romagnoli R. Baraldi P. G. Carrion M. D. Cara C. L. Cruz-Lopez O. Preti D. (2008 ). Design, synthesis, and biological evaluation of thiophene analogues of chalcones. Bioorg. Med. Chem. 16, 5367–5376.

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    Ryu H. W. Lee B. W. Curtis-Long M. J. Jung S. Ryu Y. B. Lee W. S. (2010 ). Polyphenols from Broussonetia papyrifera displaying potent α-glucosidase inhibition. J. Agric. Food Chem. 58, 202–208.

    Not in our library10.1021/jf903068k

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