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

Pharmacological Properties of Chalcones: A Review of Preclinical Including Molecular Mechanisms and Clinical Evidence Bahare Salehi 1 , Cristina Quispe 2 , Imane Chamkhi 3 , 4 , Nasreddine El Omari 5 , Abdelaali Balahbib 6 , Javad Sharifi-Rad 7 , 8 *, Abdelhakim Bouyahya 9 *, Muhammad Akram 10 , Mehwish Iqbal 11 , Anca Oana Docea 12 , Constantin Caruntu 13,14 *, Gerardo Leyva-Gómez 15 , Abhijit Dey 16 *, Miquel Martorell 17,18 , Daniela Calina 19 *, Víctor López 20,21 and Francisco Les 20,21 1 Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2 Facultad de Ciencias de La Salud, Universidad Arturo Prat, Iquique, Chile, 3 Faculty of Sciences, Mohammed V University of Rabat, Rabat, Morocco, 4 Laboratory of Plant-Microbe Interactions, AgroBioSciences, Mohammed VI Polytechnic University, Ben Guerir, Morocco, 5 Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco, 6 Laboratory of Zoology and General Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco, 7 Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 8 Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador, 9 Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University Rabat, Rabat, Morocco, 10 Department of Eastern Medicine, Government College University, Faisalabad, Pakistan, 11 Institute of Health Management, Dow University of Health Sciences, Karachi, Pakistan, 12 Department of Toxicology, University of Medicine and Pharmacy of Craiova, Craiova, Romania, 13 Department of Physiology, “Carol Davila”University of Medicine and Pharmacy, Bucharest, Romania, 14 Department of Dermatology, “Prof. N.C. Paulescu”National Institute of Diabetes, Nutrition, and Metabolic Diseases, Bucharest, Romania, 15 Departamento De Farmacia, Facultad De Química, Universidad Nacional Autónoma De México, Ciudad De México, Mexico, 16 Department of Life Sciences, Presidency University, Kolkata, India, 17 Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, Concepción, Chile, 18 Unidad De Desarrollo Tecnológico, UDT, Universidad De Concepción, Concepción, Chile, 19 Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania, 20 Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Zaragoza, Spain, 21 Instituto Agroalimentario De Aragón-IA2 CITA-Universidad De Zaragoza, Zaragoza, Spain 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 Edited by: Andrei Mocan, Iuliu Hat¸ieganu University of Medicine and Pharmacy, Romania Reviewed by: Iulia Popescu, University of Pittsburgh, United States Priyia Pusparajah, Monash University Malaysia, Malaysia *Correspondence: Javad Sharifi-Rad javad.sharifi[email protected] Abdelhakim Bouyahya [email protected] Constantin Caruntu [email protected]om Abhijit Dey [email protected]n Daniela Calina [email protected] Specialty section: This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology Received: 07 August 2020 Accepted: 12 November 2020 Published: 18 January 2021 Citation: Salehi B, Quispe C, Chamkhi I, El Omari N, Balahbib A, Sharifi-Rad J, Bouyahya A, Akram M, Iqbal M, Docea AO, Caruntu C, Leyva-Gómez G, Dey A, Martorell M, Calina D, López V and Les F (2021) Pharmacological Properties of Chalcones: A Review of Preclinical Including Molecular Mechanisms and Clinical Evidence. Front. Pharmacol. 11:592654. doi: 10.3389/fphar.2020.592654 Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926541 REVIEW published: 18 January 2021 doi: 10.3389/fphar.2020.592654 structure activity, toxicity concerns, cellular basis of mode of action, and interactions with other molecules. Keywords: chalcones, flavonoids, bioavailability, pharmacological studies, molecular mechanisms, clinical trials INTRODUCTION Chalcones are among the leading categories of flavonoids across the entire kingdom of plant (Hideo and Tatsurou, 1997;Abbas et al., 2014). The term chalcone is originated from the Greek name chalcos which means bronze. Chalcones were initially manufactured in the research lab in late 1800s (Shimokoriyama, 1962). The chalcone chemistry has created thorough scientific research all the way through the globe (Hideo and Tatsurou, 1997). Naturally existing chalcones were not separated till the year 1910 (Shimokoriyama, 1962). 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 (Schroder, 1999). 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 (Rojas et al., 2002)(Figure 1). Plants containing chalcones, for instance, the Glycyrrhiza, Piper,Angelica,andRuscus genus, have long been utilized as therapeutic remedies in Balkan countries (Schroder, 1999; Chatzopoulou et al., 2013;Maccari and Ottana, 2015). 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 (Real, 1967;Takahashi et al., 1998). 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 (Tomás-Barberán and Clifford, 2000). 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. METHODOLOGY 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,”“antiinflammatory,”“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, antiinflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive, and neuroprotective agents (Figure 2). Antidiabetic Activity In Vitro Antidiabetic Activity Several synthetic chalcones have been reported to have potential inhibitory activity against α-glucosidase or α-amylase. FIGURE 1 | General chemical structure of chalcones. Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926542 Salehi et al. Pharmacological Properties of Chalcones The IC 50 value of synthetic intermediate chalcones (1–24) varied between 15 ±0.14 and 385 ±5.60 μM(Ansari et al., 2005). Similar observations were noted with the Chana series (Bak et al., 2011), and with the tris-chalcone derivatives (5a-5i), all showing higher inhibition profiles than those of acarbose (Burmaoglu et al., 2019). Studies on hydroxyl chalcones and bis-chalcones (1a-1m) and (2a2m) were performed in connection to the inhibition kinetics (Cai et al., 2017). By using the abovementioned methods, natural chalcone derivatives (morusalbins A-D) showed significant inhibitory activities against α-glucosidase (Ha et al., 2018). 3ʹ,5ʹ-digeranylated chalcone (16) demonstrated noncompetitive inhibition characteristics (Ryu et al., 2010;Sun et al., 2015). In another study, compound 4m was found to be the most active compared to the other chalcone-triazole derivatives (Chinthala et al., 2015). Numerous studies have shown some chalcones and/or their derivatives (such as chalcone 1 with an IC 50 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 (Imran et al., 2015;Monisha et al., 2018). Chalcone units of conjugates also exhibited moderate inhibitory activities against α-glucosidase (Tang et al., 2014), with the highest activity (IC 50 3.2 ±0.2 µM) recorded by conjugate 1b. Moreover, moderate inhibitory effect was observed by piperonal chalcones derivatives against α-amylase (Acharjee et al., 2018). 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 (Attarde et al., 2014). 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 (Rocha et al., 2019). In another study, chalcone 20 was the most active inhibitor (IC 50 0.4 µM) of α-glucosidase among 20 derivatives, exhibiting noncompetitive inhibition (Seo et al., 2005;Tajuddeen et al., 2018). In addition, the inhibitory capacity of chalcones 1–13 and bis-chalcones 14–18 against α-amylase (IC 50 1.25 ±1.05–2.40 ± 0.09 µM) was found to be comparable to that of acarbose (IC 50  1.04 ±0.3 µM) (Attarde et al., 2014). Furthermore, researchers have recorded promising activities of different chalcones in inhibiting the aforementioned enzymes, occupying the active sites (Najafian et al., 2010;Rawat et al., 2011;Gomes et al., 2017). 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 (Bharatham et al., 2008). 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 (IC 50 1.2 mM) (Chatsumpun et al., 2017). A natural chalcone (lavandulylated chalcone) exhibited inhibitory activity against β-glucosidase (IC 50 57 μM) while noncompetitively inhibiting α-glucosidase (Kim et al., 2006). Similarly, another study isolated xanthohumol (XN) from Humulus lupulus L. as a potential inhibitor of α-glucosidase (IC 50 8.8 μM) reversibly and noncompetitively (Liu et al., 2014). 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 (IC 50 103.5 µM) (Rawat et al., 2011). Natural prenylchalconaringenins (1) and (2) have been investigated for their inhibitory properties against digestive enzymes; 3′-geranylchalconaringenin (2) showed moderate inhibition of α-amylase (IC 50 20.46 µM) and competitive and irreversible inhibition of α-glucosidase (IC 50 1.08 µM) (Sun et al., 2017). In addition, these two enzymes were also inhibited by three natural chalcones from Psoralea corylifolia (Mounika, 2015). Another chalcone (2ʹ,4ʹ-dihydroxy-6ʹ-methoxy-3ʹ,5ʹdimethylchalcone) (DMC) from Cleistocalyx operculatus (Roxb.) Merr. and L.M.Perry flower buds inhibited pancreatic α-amylase (IC 50 69.35) (Zhang and Lu, 2012). 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/AMPactivated protein kinase in 3T3-L1 adipocytes (Ohta et al., 2015). In Vivo Antidiabetic Activity Several authors have evaluated the antihyperglycemic activity of synthetic chalcones in streptozotocin-induced diabetic rats (Satyanarayana et al., 2004;Shukla et al., 2007;Najafian et al., 2010;Rawat et al., 2011;Mahapatra et al., 2017a;Sengupta et al., 2017;Shukla et al., 2017;Tajammal et al., 2017;Acharjee et al., 2018;Naidu, 2018;Raju et al., 2018). 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 FIGURE 2 | Summarized scheme of the most important pharmacological properties of chalcones. Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926543 Salehi et al. Pharmacological Properties of Chalcones chalcone derivative 8c (Rawat et al., 2011). Moreover, serum glucose levels were measured in hyperglycemic rats treated with chalcone analogs, which showed a significant antihyperglycemic effect (Alberton et al., 2008). In a study conducted by Damazio et al., it was evaluated the antihyperglycemic activity of nitrochalcones (Damazio et al., 2009) and naphthylchalcones (Damazio et al., 2010)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 25mg/kgdoseofchalconeadministration 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 (Jamal et al., 2009). 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 (Jayanthi et al., 2012). Chalcone derivatives (4A-4E) were tested on sucrose-loaded diabetic albino mice to find that compound 4-C (2-(3-(4methoxyphenyl)-1H-pyrazol-5-yl) phenol) achieved the most promising activity, which is supported by docking study (Jain and Jain, 2017). 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) (Ribnicky et al., 2009). Chalcone derivatives (13a-h) and (19a-h) instreptozotocininduced diabetic mice, compounds13e, 13g, and 19f reduced TG, TC, and Glu levels, respectively (Zhu et al., 2018). 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 (Shin et al., 2018). 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 (Rao et al., 2014). Significant hypoglycemic effects were displayed by five isoliquiritigenin (ISL) derivatives isolated from Glycyrrhiza glabra L. rhizomes tested in streptozotocin-induced diabetic mice (Gaur et al., 2014), chalcone-6ʹ-hydroxy-2ʹ,3,4trimethoxy-4ʹ-O-β-D-glucopyranoside (1) from Pouzolzia rugulosa (Wedd.) Acharya & Kravtsova. leaves tested in alloxan-induced diabetic mice (Semwal et al., 2009), and 2′4dihydroxy chalcone-4-glucoside from Adhatoda zeylanica Medik. flower (Purnima et al., 2012). 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-A y mice (Enoki et al., 2007;Enoki et al., 2010). 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) (Araico et al., 2006;Nyandoro et al., 2012;Bano et al., 2013; Jantan et al., 2014;Özdemir et al., 2015;Okuda-Tanino et al., 2017;Farzaneh et al., 2018). In a study to assess the antiinflammatory effect, new chalcone derivatives using carrageenan-induced hind paw edema model, the results showed that 5′-chloro-2′-hydroxy4′6′-dimethyl-3, 4, 5trimethoxychalcone (1) exhibited the most potent antiinflammatory activity with a 90% inhibition of edema (Bano et al., 2013). 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 (Özdemir et al., 2015). The nitrogen-containing chalcone derivatives showed inhibition of some enzymes implicated to inflammatory process such as β-glucuronidase, COX-2, and trypsin (Bandgar et al., 2010). 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 (Jadhav et al., 2013). 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 (Nyandoro et al., 2012). 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 LPSstimulated RAW 264.7 macrophage cells. The results showed that chalcones suppressed NO production in a dose-depending manner (Rojas et al., 2002). 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-trimethoxy20-trifluoromethylchalcone.This suggestion was supported by the data which showed an inhibition of nitrite and PGE2 levels (Rojas et al., 2003a;Rojas et al., 2003b). 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 (Daikonya et al., 2004). 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-γin a murine macrophage-like cell line (Zhao et al., 2003). Chalcones also have proved their ability to inhibit NF-κB (Gilmore, 2006;Mahapatra et al., 2017b;Chu and Guo, 2016). Other chalcone derivatives such as isoliquiritigenin, butein, and homobutein (Orlikova et al., 2012) have suppressed TNF-α mediated by the inhibition of NF-κB gene expression Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926544 Salehi et al. Pharmacological Properties of Chalcones TABLE 1 | Antidiabetic activities of chalcones: in vitro and in vivo preclinical pharmacological studies. Chalcones/source Experimental model/method Type of study Results/mechanisms Ref 1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas/synthesized STZ-induced diabetic rats In vivo Anti-hyperglycemic: ↓blood glucose level normalization of serum biochemical parameters 10–20 mg/kg, bw (Acharjee et al., 2018) Intermediate chalcones 1–24/synthesized α-Glucosidase inhibitory assay In vitro ↓α-glucosidase IC 50 15 mg/ml (Ansari et al., 2005) Chalcone derivatives (MVC1-MVC5)/synthesized Glucose uptake in yeast cells In vitro Chalcones MCV4, MCV5: ↑glucose uptake IC 50 5–15 mg/ml (Asogan and Aupati, 2016) Chalcone derivatives/synthesized STZ-induced diabetic rats In vivo Anti-hyperglycemic: ↓blood glucose level 10 mg/kg bw (Alberton et al., 2008) Chana chalcone derivatives/synthesized α-Glucosidase assay dipeptidyl peptidase-4 Adipocyte differentiation In vitro Chana 1: ↓α-glucosidase, ↓DPP-4 ↑adipocyte differentiation IC 5 250 μM/L (Bak et al., 2011) Fluoro-substituted tris-chalcones derivatives (5a-5i)/ synthesized α-Glucosidase inhibitory assay In vitro Chalcones 5a-5i: ↓α-glycosidase IC 50 22.5 μM(Burmaoglu et al., 2019) Hydroxyl chalcones and bis-chalcones (1a-1m) and (2a-2m)/synthesized α-Glucosidase assay Kinetics of enzyme inhibition Glucose level In vitro ↓α-glucosidase Chalcones 2c, 2g, 2j,2l, are noncompetitive inhibitors Chalcone2g: ↓blood glucose level (Cai et al., 2017) Prenylated chalcones (3, 4, 7) Flavanone-coupled chalcones (9, 12, 13)/natural from Boesenbergia rotunda (L.) mansf α-Glucosidase inhibitory assay In vitro ↓α-glucosidase, IC 50 1.2–20 μg/ml (Chatsumpun et al., 2017) Chalcone-triazole derivatives/synthesized α-Glucosidase inhibitory assay In vitro The most active chalcones: 4m, IC 50 67.78 μM 4p, IC 50 74.94 μM 4s, IC 50 102.10 μM (Chinthala et al., 2015) Chalcone derivatives/Synthesized STZ-induced diabetic rats In vivo ↑secretion of insulin No effects on glucose uptake into muscle No effects on blood glucose levels 50 mg/kg bw (Damazio et al., 2009) Naphthylchalcones/synthesized STZ-induced diabetic rats In vivo ↑glucose tolerance curve ↑secretion of insulin 10 mg/kg bw (Damazio et al., 2010) Xanthoangelol (XA) and 4-hydroxyderricin (4HD)/ natural from Angelica keiskei (miq.) koidz STZ-induced diabetic Mice In vivo Chalcone 4HD: ↓blood sugar level No effects on secretion of insulin diet containing 0.15% chalcone 4HD (Enoki et al., 2010) Five derivatives from isoliquiritigenin (ISL)/natural from Glycyrrhiza glabra L STZ-induced diabetic Mice In vivo Anti-hyperglycemic: ↓blood glucose level 100 mg/kg bw (Gaur et al., 2014) Chalcone derivatives: four DAs (morusalbins A−D)/ natural from Morus alba L. α-Glucosidase inhibitory assay In vitro DAs (1–4, 6–8, 11, 12, 14), DAs (4, 6–8): ↓α-glucosidase IC 50 2.25–5.90 μM (Ha et al., 2018) Chalcone 1/synthesized α-Glucosidase inhibitory assay In vitro ↓α-glucosidase, IC 50 840 μM, compared with acarbose IC 50 860.25 ±6.20 μM (Imran et al., 2015) Chalcones: BUT, ISL, DHC, HDMC, DCC, DCCP, CMC, CMCP/synthesized STZ-induced diabetic rats In vivo ↓glycogen content in liver 25 mg/kg bw (Jamal et al., 2009) 2hydroxychalcone/synthesized HFD-induced diabetic rats In vivo ↓secretion of insulin ↑glycosylated hb, ↑glucose blood level 25 mg/kg bw (Jayanthi et al., 2012) Lavandulylated chalcone/natural from Sophora flavescens aiton α-Glucosidase β-amylase β-galactosidase α-amylase inhibitory assays In vitro ↓β-galactosidase, IC 50 57 μM↓α-glucosidase, noncompetitive inhibition ↓β-amylase, mixed inhibition IC 50 57 μM (Kim et al., 2006) Xanthohumol (XN)/natural from Humulus lupulus Lα-Glucosidase inhibitory assay In vitro ↓α-glucosidase; reversible, noncompetitive IC 50 8.8 μM (Liu et al., 2014) Chalcone derivatives/synthesized α-Amylase α-glucosidase inhibitory assays In vitro ↓α-amylase, ↓α-Glucosidase IC 50 1250 μg/ml (Monisha et al., 2018) Diarylsulfonylurea-chalcone hybrids/synthesized STZ-induced diabetic rats In vivo Anti-hyperglycemic: ↓blood glucose level 10, 30, 50 mg/kg bw (Naidu, 2018) Trans-chalcone (benzylideneacetophenone) STZ-induced diabetic Rats In vivo Anti-hyperglycemic: ↓blood glucose level ↑ moderate secretion of insulin 2, 8, 16, 32 mg/kg bw (Najafian et al., 2010) 4-Hydroxyderricin (4HD) xanthoangelol (XAG)/natural from Angelica keiskei (miq.) koidz 3T3-L1 adipocytes In vitro Chalcones 4HD, XAG: ↑glucose uptake GLUT4dependent through the LKB1/AMPK signaling pathway IC 50 20 μmol/L (Ohta et al., 2015) Chalcones AC1-AC11, BC1BC6) 2′, 4-dihydroxy chalcone -4-glucoside/synthesized and natural from Justicia adhatoda L Measuring the glucose diffusion In vitro All chalcones: Good anti-hyperglycemic effect AC6: The highest activity IC 50 100 μg/ml (Purnima et al., 2012) Chalcones (6, 7, 20)/natural from Derris indica (lam.) bennet α-Glucosidase inhibitory assay In vitro ↓α-glucosidase chalcone 6: IC 50 103.5 μM(Romagnoli et al., 2008) Sulfonylurea chalcones 1–3/synthesized Normoglycemic rabbits In vivo All compounds: Hypoglycemic activity Compound3: The highest activity (38.73%) 5 mg/kg bw (Rao et al., 2014) 30-C-b-dglucopyranosyldihydro chalcone (22)/ synthesized STZ-induced diabetic rats In vivo Chalcone 22: ↓blood glucose (comparable to metformin), 25 mg/kg bw (Rawat et al., 2011) (Continued on following page) Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926545 Salehi et al. Pharmacological Properties of Chalcones (Orlikova et al., 2012). Isoliquiritigenin also reduced palmitic acid–induced macrophage activation, leading to additional antiinflammatory activity (Watanabe et al., 2016). In human primary endothelial cells Isoliquiritigenin prevented the translocation and stimulation of NF-κB by hindering the phosphorylation and subsequent decomposition of IkBα(Kumar et al., 2007). Antimicrobial and Antifungal Activity From the leaves and stems of Crotalaria madurensis Wight & Arn., crotmadine (1) was isolated that exhibited antifungal activity (Bhakuni and Chaturvedi, 1984). 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 (Svetaz et al., 2004). The antifungal activity of the chalcones (9–13), extracted from the methanol extract of the leaves of Artocarpus nobilis Thwaites, showed potent fungicidal activity (Jayasinghe et al., 2004). 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 (Kulkarni et al., 2014). The extracted compounds from Zuccagnia punctata Cav. were found to be efficacious as inhibitors of Candida species (Gabriela et al., 2014). 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 TABLE 1 | (Continued) Antidiabetic activities of chalcones: in vitro and in vivo preclinical pharmacological studies. Chalcones/source Experimental model/method Type of study Results/mechanisms Ref 2′,4′- dihydroxy-4-methoxydihydrochalcone (DMC2)/synthesized HFD obese C57BL/6J male mice In vivo ↓blood glucose (comparable to metformin) 200–300 mg/kg bw (Ribnicky et al., 2009) Chalcones (1–4)/natural from Broussonetia papyrifera (L.) L’Hér. Ex vent α-Glucosidase inhibitory assay In vitro Chalcones 1: ↓α-glucosidase, IC 50 5.3 μM Chalcones 2: ↓α-glucosidase, IC 50 11.1 μM (Ryu et al., 2010) Chalcones (5a-r), (4a-e), (3a-e)/synthesized HFD sucrose STZ-induced diabetic rats In vivo Chalcones 5a, g, m, o, p, r Anti-hyperglycemic: ↓blood glucose level 100 mg/kg bw (Satyanarayana et al., 2004) Chalcone-6ʹ-hydroxy-2ʹ,3,4-trimethoxy-4ʹ-O-β-Dglucopyranoside (1)/natural from Pouzolzia rugulosa (wedd.) acharya and kravtsova Alloxan-induced diabetic mice In vivo Hypoglycemic activity 100, 200, 500 mg/kg bw (Semwal et al., 2009) 1-{4-[(2E)-3-(substituted phenyl) prop-2enoyl] phenyl}-3-(substituted phenyl”) urea (2a-d), 3(a-c)/ synthesized STZ-induced diabetic Rats In vivo Anti-hyperglycemic: ↓blood glucose level doses of compounds 2(a-d) and (a-c) 35 mg/kg bw (Sengupta et al., 2017) Chalcone derivatives (1–20)/synthesized α-Amylase, α-glucosidase β-amylase inhibitory assays In vitro Chalcone 20: ↓α-glucosidase IC 50 0.4 μM, noncompetitive inhibition (Seo et al., 2005) Trihydroxychalcone derivatives/synthesized C2C12 myotubes cells HFD diabetic C57BL/6 mice In vitro In vivo Chalcone 13: ↑AMPK→↑AMP-activated C 50 10 μmol/L protein kinase; ↑glucose tolerance, ↑muscle FAO, ↓fat in skeletal muscles, liver 30 mg/kg bw (Shin et al., 2018) Chalcone-based aryloxypropanolamines (5a-n)/ synthesized HFD sucrose and STZ-induced diabetic rats In vivo Anti-hyperglycemic: ↓blood glucose level (Shukla et al., 2007) Chalcone-based aryloxy-propanolamines3, 9(a, b), 10/synthesized HFD sucrose and STZ-induced diabetic rats In vivo Chalcone 9a: ↑glucose tolerance in sucrose HFD sucrose feeded rats Chalcones 3, 9a, 9b: ↑ postprandial hyperglycaemia in STZ-induced diabetic rats 100 mg/kg bw (Shukla et al., 2017) 3′,5′-digeranylated chalcone (16)/synthesized α-Glucosidase inhibitory assay In vitro ↓α-glucosidase, interaction chalcone 16 and α-glucosidase’sIC 50 0.90 μM (Sun et al., 2015) Prenylchalconaringenins (1) and (2)/natural α-Amylase, α-glucosidase inhibitory assays STZ-induced diabetic mice In vitro In vivo 3′-Geranylchalconaringenin (2) ↓α-amylase, IC 50 20.46 μM↓α-glucosidase, IC 50 1.08 μM ↓postprandial blood glucose, ↓TG, ↓cholesterol 60 mg/kg bw (Sun et al., 2017) Chalcones (2a, 2b, 2c)/synthesized STZ-induced diabetic Rats In vivo Chalcone 2a: ↓blood glucose level, antihyperglycemic in diabetic rats Chalcone 2c: ↓blood glucose level in normoglycemic rats 100 mg/kg bw (Tajammal et al., 2017) Chalcone units of conjugates/synthesized α-Glucosidase inhibitory assay In vitro All chalcones: ↓α-glucosidase Chalcone 1b:↑ inhibitory activity IC 50 3.2 μM (Tang et al., 2014) 2ʹ,4ʹ-dihydroxy-6ʹ-methoxy-3ʹ,5ʹ-dimethylchalcone (DMC)/natural from Cleistocalyx operculatus (roxb.) merr. and L.M.Perry α-Amylase inhibitory assay In vitro DMC: ↓pancreatic α-amylase IC 50 69 μM(Zhang and Lu, 2012) Chalcone derivatives (13a-h), (19a-h)/synthesized STZ-induced diabetic Mice In vivo Chalcones 13e, 13g, 19f; ↓TG, ↓TC, ↓Glu Chalcones 13e,19f: ↑AMPK, ↑PPARα50 mg/kg bw (Zhu et al., 2018) Abbreviations and symbols: ↑, increased; ↓, decreased; STZ, streptozotocin; MD, molecular dynamic simulations; HFD, high fructose diet; GLUT-4, glucose transporter type 4; LKB1, liver kinase B1; AMPK, AMP-activated protein kinase; PPARα, peroxisome proliferator-activated receptors; BW, body weight. Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926546 Salehi et al. Pharmacological Properties of Chalcones fungi probably by inhibiting the biosynthesis of one or both polymers of the fungal cell wall (Lopez et al., 2001). A large series of chalcones were synthesized and studied for antifungal activity against Candida albicans; the chalcones (60–64) exhibited promising anti-candidal activities (Batovska et al., 2007). 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 (Liaras et al., 2011). 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 (Siddiqui et al., 2012). Using the agar cupplate method, the antimicrobial activities of the synthesized compounds (95–106) were screened in vitro. The results exhibited promising antifungal activity and antibacterial activity (Prasath et al., 2013). Compound 107 was evaluated for its antibacterial properties and showed maximum zone of inhibition against S. aureus and P. aeruginosa (Bhale et al., 2013). A series of a-triazolyl chalcones were synthesized (108–121), and the synthesized compounds showed potent antibacterial activity TABLE 2 | Anti-inflammatory activities of chalcones. Chalcones/source Mechanism Results Ref 5′-Chloro-2′-hydroxy-4′6′-dimethyl-3, 4, 5 -Trimethoxy-chalcone/synthesized ↓COX-1 ↓COX-2 ↓TNF-α IC 50 87.6 µM IC 50 88.0 µM IC 50 5–10 µM (Bano et al., 2013) 3-(5-bromo-1H-indol-3-yl)-1-(4-cyanophenyl) prop-2-en-1-one/synthesized ↓COX-1 ↓COX-2 IC 50 23.2 ±0.5 μg/ml IC 50 27.1 ±2.5 μg/ml (Özdemir et al., 2015) (5-Methoxy-1H-indol-3-yl)-1-(4-(methylsulfonyl) phenyl) prop-2-en-1-one/ synthesized ↓COX-1 IC 50 24.5 μg/ml no effect on COX-2 (Özdemir et al., 2015) Hydroxy-3,4,6-trimethoxychalcone/natural from Toussaintia orientalis verdc ↓COX-1 IC 50 9565 μg/ml no effect on COX-2 (Nyandoro et al., 2012) Licochalcone A/natural from Glycyrrhiza inflata batalin ↓COX-1 ↓COX-2 IC 50 0.94 μg/ml IC 50 1.93 μg/ml (Okuda-Tanino et al., 2017) (E)-3-(4-((ethylamino)methyl)-phenyl) -1-(5-methylfuran-2-yl)prop-2-en-1-one/ synthesized ↓COX-1 ↓COX-2 IC 50 25.85 μg/ml IC 50  10.08 μg/ml (Jantan et al., 2014) Ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one/synthesized ↓COX-2 IC 50 0.05 μg/ml no effect on COX-1 (Farzaneh et al., 2018) (E)-4-methyl-N-((4-(3-(3,4,5 trimethoxyphenyl) acryloyl)phenyl)-carbamoyl) benzenesulfonamide (Me-UCH5)/synthesized ↓COX-2 IC 50 0.06 μg/ml no effect on COX-1 (Araico et al., 2006) (E)-1-(2,6-dimethoxyphenyl)-3-(4-(dimethylamino)phenyl)prop-2-en-1-one/ synthesized ↓PGE2 IC 50 0.6 µM (Rojas et al., 2002) (E)-1-(2,5-dimethoxyphenyl)-3-(4-(dimethylamino)phenyl)prop-2-en-1-one/ synthesized ↓PGE2 IC 50 0.7 µM (Rojas et al., 2002) 3,4,5-Trimethoxy-4′-fluorochalcone/synthesized ↓PGE2 IC 50 0.033 µM (Rojas et al., 2003b) 1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8yl]-3-(4-hydroxy-phenyl)- propanone/natural Mallotus philippinensis ↓PGE2 IC 50 7.6 µM (Daikonya et al., 2004) 3-(3,4-dihydroxy-phenyl)-1-[6-(3,7-dime-thyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2dimethyl-2H-chromen8-yl]-propenone/natural Mallotus philippinensis ↓PGE2 IC 50 9.5 µM (Daikonya et al., 2004) 1-[5,7-dihydroxy-2-methyl-6-(3-methyl-but-2-enyl)-2-(4-methyl-pent-3-enyl)-2Hchromen-8-yl]-3-(3,4dihydroxy-phenyl)-propenone/natural Mallotus philippinensis ↓PGE2 IC 50 38.6 µM (Daikonya et al., 2004) Broussochalcone A/natural from Broussonetia papyrifera (L.) L’Hér. Ex vent ↓PGE2 IC 50 11.3 µM (Chen et al., 2017) Isobavachalcone/natural from Cullen corylifolium (L.) medik ↓PGE2 IC 50 1.6 ±0.11 µM (Kim et al., 2018) Bavachromene/natural from Cullen corylifolium (L.) medik ↓PGE2 IC 50 2.4 ±0.18 µM (Kim et al., 2018) Kanzonol B/natural from Cullen corylifolium (L.) medik ↓PGE2 IC 50 2.2 ±0.21 µM (Kim et al., 2018) (3-(2-Hydroxyphenyl)-1-(thiophene-3-yl)prop-2-en-1-one) (TI-I-174)/synthesized ↓PGE2 IC 50 5.75 µM (Kim et al., 2014) 2-(3-(3,4-dimethoxyphenyl)propyl)-5-methoxyphenol/synthesized ↓PGE2 IC 50 6.5 µM (Vijaya Bhaskar Reddy et al., 2017) (E)-1-(4-hydroxy-3-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one/ synthesized ↓PGE2 IC 50 4.19 µM (Hara et al., 2014) (E)-1-(3-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one/synthesized ↓PGE2 IC 50 2.88 µM (Hara et al., 2014) 2′-methoxy-3,4-dichlorochalcone/synthesized ↓PGE2 IC 50 7.1 µM (Kim et al., 2007) 2′-hydroxy-6′-methoxychalcone/synthesized ↓PGE2 IC 50 9.6 µM (Kim et al., 2007) 2′-hydroxy-3-bromo-6′-methoxychalcone/synthesized ↓PGE2 IC 50 7.8 µM (Kim et al., 2007) 2′-hydroxy-4′,6′-dimethoxychalcone/synthesized ↓PGE2 IC 50 9.6 µM (Kim et al., 2007) 2′,5′, -dihydroxy-4-chloro-dihydrochalcone/synthesized ↓PGE2 IC 50 4.0 ±1.5 µM (Huang et al., 2001) 4-hydroxylonchocarpin/natural from Psoralea corylifolia L↓PGE2 IC 50 10.2 µM (Lee et al., 2005) Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926547 Salehi et al. Pharmacological Properties of Chalcones and antifungal activity (Yin et al., 2014). 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 (Kucerova-Chlupacova et al., 2015). 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 (Singh et al., 2018). 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 (Koudokpon et al., 2018). A series of ten chalcones and five new dihydrochromane–chalcone hybrids (189–203) were synthesized, and their antifungal activity was evaluated in vitro,andonlytwo compounds had similar antifungal activity to that of the positive control (Mellado et al., 2019). 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 (Amole et al., 2019). Antiparasitic Activity Antileishmanial Activity The in vitro antileishmanial activity of chalcones was evaluated by several studies (Torres-Santos et al., 1999;Salem and Werbovetz, 2005;Salem and Werbovetz, 2006;Lima et al., 2016). Licochalcone inhibited the growth of both Leishmania major and Leishmania donovani promastigotes and amastigotes and reduced the infection rate of human peripheral blood monocytederived macrophages (Chen et al., 1993). Adunchalcone displayed 50% effective concentrations against the promastigote forms of Leishmania (L.) amazonensis,L(V.) braziliensis,L(V.) shawi, and L(L.) chagasi, respectively (Dal Picolo et al., 2014). In another study, chalcones obtained Psorothamnus polydenius (S.Watson) Rydb., and exhibited leishmanicidal properties (Salem and Werbovetz, 2005). The chalcone 2,6′-Dihydroxy-4’-methoxychalcone (DMC) showed significant activity against promastigotes and intracellular amastigotes of Leishmania amazonensis (Torres-Santos et al., 1999). Many other chalcone-derived plants displayed varying degrees of leishmanicidal activity such as isoliquiritigenin (Salem and Werbovetz, 2006), chalcone from Lonchocarpus xuul Lundell TABLE 3 | Antileishmanial activity of chalcones. Chalcones/source Type of study Tested effects Parasite Ref Licochalcone/natural In vitro L. donovani promastigotes amastigote form of L. major IC50 2.4 μg/ml (Chen et al., 1993) 2′,6′-dihydroxy-4′-methoxychalcone (DMC, 2)/ natural In vitro L. amazonensis promastigotes Damages of cell ultrastructure IC50 50 μg/ml: Damage to amastigote mitochondria IC50 40 μg/ml: Damage to promastigote mitochondria (Torres-Santos et al., 1999) Dihydrochalcones, 2′,6′-dihydroxy-4′- methoxydihydrochalcone 4/natural In vitro L. infantum promastigotes IC50 15.30 μg/ml (Hermoso et al., 2003) 2’,6’,4-trihydroxy-4′-methoxydihydro chalcone (5)/ natural In vitro L. tropica promastigotes L. infantum promastigotes IC50 3.82 μg/ml IC50 6.35 μg/ml (Hermoso et al., 2003) Chalcones from Psorothamnus arborescens (A.Gray) barneby/natural In vitro L. donovani amastigotes IC50 5.0 μg/ml (Salem and Werbovetz, 2005) Isoliquiritigenin/natural In vitro L. donovani amastigotes IC50 5.30 μg/ml (Salem and Werbovetz, 2006) Chalcone from Lonchocarpus guatemalensis benth/ natural In vitro L. braziliensis promastigotes IC50 10 μg/ml (Borges-Argaez et al., 2007) Chalcone-triclosan hybrids/semisynthetic In vitro L. panamensis IC50 9.4 ±1.3 μM(Otero et al., 2014) 2′,4′-dihydroxychalcone 35/synthesized In vitro L. amazonensis promastigotes IC50 0.4 μM(Passalacqua et al., 2015) Methoxychalcones/synthesized In vitro L. braziliensis promastigote IC50 <10 μM(Bello et al., 2011) (1E,4E)-1,5-bis(3,4,5-trimethoxy-phenyl)-penta-1,4dien-3one/synthesized In vitro L. (Viannia) braziliensis IC50 1.38 ±1.08 μM(de Mello et al., 2014) (1E,4E)-1,5-bis(phenyl)-penta-1,4-dien-3-one/ synthesized In vitro L. (Viannia) braziliensis IC50 5.88 ±1.35 μM(de Mello et al., 2014) (2E)-1-phenyl-3-(3,4,5-trimethoxy-phenyl)-prop-2en-1one/synthesized In vitro L. (Viannia) braziliensis IC50 6.36 ±2.04 μM(de Mello et al., 2014) (2E)-1-(4-methoxy-phenyl)-3-(3,4,5-trimethoxyphenyl)- prop-2-en-1-one/synthesized In vitro L. (Viannia) braziliensis IC50 5.69 ±0.20 μM(de Mello et al., 2014) Chalcone 22 Chromenochalcones/synthesized In vivo L. donovani/hamster model 50 mg/kg/day→↓parasites 48.53 ± 10.43% on day 7 post treatment (Gupta et al., 2014) Chalcone 37 Chromenochalcones/synthesized In vivo L. donovani/hamster model 50 mg/kg, for10 days→↓parasites (83.32 ±12.37%) (Gupta et al., 2014) Chalcone-triclosan hybrids/semisynthetic In vitro L. panamensis IC50 9.4 ±1.4 μg/ml (Otero et al., 2014) Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926548 Salehi et al. Pharmacological Properties of Chalcones (Borges-Argaez et al., 2007), chalcones from Calea uniflora Less (family Compositae) (Lima et al., 2016), and sulfonamide 4methoxychalcone derivatives (Andrighetti-Fröhner et al., 2009). A series of oxygenated chalcones demonstrated remarkable antileishmanial activity (Liu et al., 2003). 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 (Otero et al., 2014). The compounds of methoxychalcones and another synthetic chalcone, 2’,4′-dihydroxychalcone displayed potent in vitro antileishmanial activity (Bello et al., 2011; Passalacqua et al., 2015). 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 (Chen et al., 1994; TABLE 4 | Antimalarial activity of chalcones. Chalcones Source Method Type of study Parasite Effects Ref Bartericin A1 Natural Culture W2 strain of P. falciparum In vitro P. falciparum IC 50 2.15 ±0.02 μM(Ngameni et al., 2007) Bartericin B2 Natural Culture W2 strain of P. falciparum In vitro P. falciparum IC 50 19.27 ±0.06 μM(Ngameni et al., 2007) Stipulin 3, 4 Natural Culture W2 strain of P. falciparum In vitro P. falciparum IC 50 5.13 ±0.04 μM(Ngameni et al., 2007) Hydroxylonchocarpin 4 Natural Culture against the W2 strain of P. falciparum In vitro P. falciparum IC 50 3.36 ±0.07 μM(Ngameni et al., 2007) Isobavachalcone 5 Natural Culture against the W2 strain of P. falciparum In vitro P. falciparum IC 50 19.00 ±0.02 μM(Ngameni et al., 2007) Kanzonol B Natural Culture against the W2 strain of P. falciparum In vitro P. falciparum IC 50 9.63 ±0.04 μM(Ngameni et al., 2007) Cajachalcone Natural The bioassay-guided fractionation of methanol extract of C. cajan leaves In vitro P. falciparum IC 50 2.0 µg/mL (Ajaiyeoba et al., 2013) Xanthohumol and seven derivatives Semi - Synthetic —In vitro P. falciparum IC 50 8.4 ±0.3 μM (poW) IC 50 24.0 ±0.7 μM (Dd2) (Frölich et al., 2009) Sulfonamide chalcone derivatives Synthetic Culture of P. falciparum parasites In vitro P. falciparum IC 50 >10 μM(Domínguez et al., 2005) Sulfonamide chalcone derivatives Synthetic b-hematin formation In vitro P. falciparum IC 50 0.48 μM(Domínguez et al., 2005) Quinolinyl chalcones derivatives Synthetic Culture of P. falciparum parasites In vitro P. falciparum IC 50 19.0 μM (Domı nguez et al., 2001) Hlorovinyl sulfone-like chalcone derivatives Synthetic Claisen–Schmidt condensation In vitro P. falciparum IC 50 0.025–10 mM (Dominguez et al., 2009) Phenylurenyl chalcone Synthetic - In vitro P. falciparum IC 50 1.76 μM(Domínguez et al., 2005) -(2,5-dichlorophenyl)-3-(4-quinolinyl)-2propen-1-one Synthetic - In vitro P. falciparum IC 50 200 nM (Li et al., 1995) Chloroquinoline Synthetic Claisen–Schmidt condensation In vitro P. falciparum IC 50 31.54 mM (Hayat et al., 2011) 1-(4-Benzimidazol-1-yl-phenyl)-3-(2, 4dimethoxy-phenyl)-propen-1-one Synthetic Claisen–Schmidt condensation In vitro P. falciparum IC 50 1.1 μg/ml (Yadav et al., 2012) Licochalcone Synthetic —In vitro P. falciparum IC 50 1.43 μg/ml (Yadav et al., 2012) Acridinyl chalcone derivatives (1a–k) Synthetic Noncatalyzed nucleophilic aromatic In vitro p falciparum IC 50 2 mg/ml (Tomar et al., 2010) Chalcone-AZT hybrid series 7 and 9Acetylenic chalcones (1a–c, 2a–e) Chalcone-chloroquinoline hybrid compounds (8 and 10) Synthetic - —In vitro p falciparum Compound 8b was the most active, submicromolar IC 50 values against the D10, Dd2 and W2 strains of P. falciparum. (Guantai et al., 2010) Alkoxylated Chalcones Synthetic - In vitro P. falciparum IC 50 6.5 mM (Nowakowska, 2007) 4-Chloro-20,40-dihydroxychalcone Synthetic - In vitro P. falciparum IC 50 12.3 mM (Nowakowska, 2007) Hydroxylated chalcones Synthetic - In vitro P. falciparum IC 50 20 mM (Nowakowska, 2007) Phenylurenyl chalcone derivatives Synthetic - In vitro P. falciparum IC 50 1.75–10 mM (Nowakowska, 2007) Xanthohumol Synthetic - In vitro P. falciparum IC 50 8.2 mM IC 50 24 mM (Nowakowska, 2007) Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 5926549 Salehi et al. Pharmacological Properties of Chalcones Araico,A.,Terencio,M.,Alcaraz,M.,Dominguez,J.,Leon,C.,andFerrandiz,M.(2006). Phenylsulphonyl urenyl chalcone derivatives as dual inhibitors of cyclo-oxygenase-2 and 5-lipoxygenase. Life Sci. 78, 2911–2918. doi:10.1016/j.lfs.2005.11.017 Asogan, M. V., and Aupati, V. R. (2016). 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The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 11 | Article 59265421 Salehi et al. Pharmacological Properties of Chalcones