- Review
- Open access
- Published:
Flavonoids: isolation, characterization, and health benefits
Beni-Suef University Journal of Basic and Applied Sciences volume 9, Article number: 45 (2020)
Abstract
Background
The unique and vast pharmacological activities of flavonoids have made them of research interest. This led to the use of various techniques to isolate and characterize them, intending to determine their potential health benefits.
Main text
The medicinal values of plant-based flavonoids that this literature review tends to summarize the pharmacological activities of these secondary metabolites from 22 selected plant families. The pharmacological shreds of evidence reported in the literature have proven that flavonoids have shown anti-cancer, anti-microbial, anti-oxidant, anti-inflammatory, anti-fungal, anti-ulcer, and anti-edematogenic activities. Out of these, 30% showed to have anti-oxidant activity, key in protecting the body against free radicals. Besides, 18% of the references showed anti-microbial and anti-cancer activities. Further literature reports indicated that flavonoids from these families exhibited anti-inflammatory and anti-edematogenic (9%), anti-viral and anti-ulcer (5%), anti-fungal, anti-nociceptive, and anti-histamine (2%).
Conclusion
The pharmacological activities of flavonoids from the various sources reviewed in this study show that the secondary metabolites could provide a scaffold for the development of potent anti-cancer drugs in the future.
1 Background
Flavonoids are phytochemicals responsible for the various colors in the seeds, flowers, fruits, leaves, and bark [1]. Flavonoids are a large class of natural aromatic compounds as there are reported to be the most common plants’ phenolics [2, 3]. Over the years, flavonoids have represented a vast percentage of phytochemicals from natural sources. It has been reported that more than 10,000 different classes of flavonoids have been found in kingdom Plantae [4,5,6]. Flavonoids are secondary metabolites found in organs of these plants with different functions [7, 8]. Also, they have been reported from sources such as vegetables, wine, fruits, and beverages (tea) [9].
The chemical structures of flavonoids consist of C6-C3-C6 [10] rings which correspond to two aromatic rings A and B linked by three carbon atoms, which may lead to the formation of a third ring (C). Variations in this basic structure give the various subclasses of flavonoidal compounds. These are flavanones, isoflavones, flavones, flavanols (catechins), chalcones, flavonols, and anthocyanins [11,12,13,14]. The flavonoids present in the diet help in the prevention of cardiovascular disease [15]. The biological and oxidative properties of flavonoids are responsible for their anti-allergic, cardioprotective, anti-diabetic, anti-inflammatory, anti-oxidative activity, and free radical scavenging capacity [15, 16]. Also, flavonoids have been reported to exhibit anti-cancer activity [5]. Studies of flavonoids revealed that they are free radical scavengers and reducing agents [17]. Recent researches have focused on the health benefits of these secondary metabolites because of their preventive activity against diseases and anti-oxidative activity, anti-cancer activities, anti-viral activities, and anti-inflammatory [18, 19]. Aside from the anti-oxidant activity of flavonoids, chelating properties [20], their usage as anti-aging substances [21], capillary permeability, and inflammatory response [22], anti-bacterial and therapeutic [23], gastro-protective, and anti-diabetic activity [3] of these phenolics have been reported.
The protective effects such as the anti-inflammatory, anti-oxidant, anti-viral, and anti-tumor activity of flavonoids from natural sources are well documented [24]. The anti-carcinogenic activity of flavonoids has been linked to their anti-oxidant properties [25] which is due to the hydroxyl groups on the structure of the flavonoids [26]. Because of the importance of these phytochemicals, this review summarizes the isolation, characterization, and health benefits of these flavonoids taking into consideration those phytochemicals responsible for these activities. The health benefits reviewed were anti-cancer, anti-microbial, anti-oxidant, anti-inflammatory, anti-fungal, anti-ulcer, and anti-edematogenic activities.
2 Main text
2.1 Methods
The search was done by using keywords such as flavonoids on “science direct,” “google scholar,” “Scopus” database, and many journal sites. Journals employed in the search are Elsevier and Springer. Other search engines used as well as papers published between 2006 and 2019.
3 Results
3.1 Flavonoids biosynthetic pathway
Flavonoids or stilbenes biosynthetic pathway (Fig. 1) follow the extension of 4-hydroxycinnamoyl-CoA with three malonyl-CoA units, in which the poly-β-keto chain folded in different ways, via Aldo or Claisen reactions. Stilbene synthase and chalcone synthase (enzymes) couple the three malonyl-CoA with cinnamoyl-CoA unit to give chalcones or stilbene. Chalcones are precursors for the vast range of flavonoids and their derivatives found in plants. The nucleophilic attack (Michael type) of a phenolic group on α, β-unsaturated ketone forms a six-membered heterocyclic ring such as naringenin. This isomerization reaction in an acid condition favors the flavanone while in basic condition, the chalcone [27]. Flavanones then give rise to variants of flavonoids such as flavonols, flavones, anthocyanidins, and catechins as shown in Fig. 1
3.2 Sources and classification of flavonoids
The various sources of flavonoids have been reported [28] and are given in Table 1 while their classification [29] is shown in Table 2 showing the subclasses. Similarly, Fig. 2 showed the basic skeleton of flavonoids and their various classes.
3.3 Isolation of flavonoids
The isolation of flavonoids involves various techniques available to natural products researchers that have simplified their isolation from crude extracts. These techniques are column chromatography (CC), high-performance liquid chromatography (HPLC), high-speed counter-current chromatography (HSCCC), counter-current chromatography (CCC), open centrifugal preparative thin layer chromatography (CPTLC), preparative thin-layer chromatography (PTLC), medium pressure liquid chromatography (MPLC), and high-pressure preparative liquid chromatography (HPLC) [29, 30]. The details of the extraction, steps, and the solvents used for the structural elucidation and characterization of the flavonoids summarized in this review are shown in Table 5.
3.4 Techniques used to elucidate the structure of flavonoids
Natural products researchers use the following spectroscopic techniques to elucidate the structure of flavonoids. These are infrared spectroscopy (IR), nuclear magnetic resonance (NMR), ultra-violet spectrophotometry (UV), mass spectrometry (MS), and physical properties as electronic circular dichroism (ECD), melting point (m.pt), and specific rotation power \( \Big({\left[\alpha \right]}_D^T \)) for flavonoids with a stereocenter for ECD and [α]D. Flavonoids have unique chemical shifts. These characteristic chemical shifts make it easier to characterize them. The characteristic chemical shift values reported [29] for some flavonoid classes are given (Table 3) and the UV absorption ranges for these flavonoids are shown (Table 4).
The isolation, characterization, and health benefits of these flavonoids are represented (Scheme 1).
4 Discussion
4.1 Health benefits of flavonoids
Extensive biological studies of flavonoids have revealed their health benefits including disease prevention [5, 72]. They have exhibited anti-oxidant, anti-inflammatory, anti-bacterial, and anti-viral activities [73], anti-oxidant [74], anti-allergic anti-carcinogenic properties [75]. The protective effects of flavonoids have been reported as they help to reduce oxidative stress in the body. The cholesterol-lowering activity, anti-cancer, anti-oxidant of myricetin, tricin, apigenin, luteolin, quercetin, and isorhamnetin has been reported [24]. The anti-viral, anti-bacterial, anti-cancer, cardioprotective, and anti-inflammatory activity [76], as chelating agents and, are strong topoisomerase inhibitors [24] anti-aggregational, anti-atherosclerotic, and detoxification activities [77] of various flavonoids have been reported. These biological activities depend to a larger extent on the hydroxyl group in the flavonoids [78]. Quercetin has reduced the risk of cancer, eye diseases, arthritis, and allergic disorders [9]. The decreased risk of cardiovascular disease by proanthocyanins and flavone-3-ols has been reported [23]. The techniques used for the isolation, characterization, and the health benefits of these flavonoids are as shown in Table 5.
The pharmacological activities of the phytochemical constituents from 22 plant families reported in the literature as reviewed in Fig. 3 showed the percentages of these activities. Out of the references cited, 30% of the flavonoids showed anti-oxidant activity. Because of this vast anti-oxidant activity, flavonoids reduce aging by protecting the body against free radicals oxidation [26, 79].
4.2 Anti-oxidant activity
Anti-oxidants are compounds that slow or prevent oxidation in living cells. They act against the effects of free radicals. Flavonoids protect the body against reactive oxygen species. Chemically, flavonoids have hydroxyl groups and a highly conjugated π-electron system, which allows them to act as free radical scavengers [80]. Anti-oxidant activity of flavonoids [16, 20, 33, 76, 81], chelating properties [20], makes them acts as protective agents against free radicals [26, 79]. In the body, anti-oxidants protect the human body from free radicals oxidation [17] thereby retarding the progress of many chronic diseases. Epicatechin, epigallocatechin, and gallocatechin have exhibited anti-oxidant activity [31].
Naringenin has shown anti-oxidant, anti-diabetic, anti-atherogenic, anti-depressant, immunomodulatory, antitumor, antiinflammatory, and hypolipidaemic, activity [12]. Catechin, epicatechin, rutin, quercetin, and naringin have been reported for anti-oxidant activity against free radicals [32]. The anti-oxidant activity of spectaflovoside A, kaempferol-3-O-(2′′,3′′-di-O-acetyl)-α-L-rhamnopyranoside, kaempferol-3-O(3′′,4′′-di-O-acetyl)-α-L-rhamnopyranoside, kaempferol-3-O- (2′′,4′′-di-O-acetyl)-α-L-rhamnopyranoside, kaempferol, and kaempferol-3-O-(4′′-Oacetyl)-α-L-rhamnopyranoside were documented [36]. The anti-oxidant activity of flavonoids extracted from Phlomis bovei De Noé [82], quercetin, taxifolin, catechin, and galangin, anthocyanidin, kaempferol, catechins, and catechin gallate esters have been reported [83]. Quercetin, anthocyanidin and kaempferol, catechins, and catechin gallate esters are effective anti-oxidants against free radicals. Quercetin had showed excellent in vitro anti-oxidant capacity [59]. Quercimeritrin, scutellarein, and rutin isolated from C. angustifolia showed strong anti-oxidant activity against oxidative stress [54]. The phytochemical investigation of the ethanol extract of Ximenia parviflora Benth. Var led to the isolation of quercetin, kaempferol, and apigenin with anti-oxidant activity. Similarly, the naringenin, quercetin, and kaempferol isolated from the ethanolic extract of Viscum album L showed anti-oxidant activity [62]. Catechins have been reported for its protection against oxidative stress, cancer, and cardiovascular disorder [84]. In Fig. 4, the chemical structures of flavonoids reported for their benefits are as shown.
4.3 Anti-microbial activity
The broth microdilution assay of spectaflovoside A, kaempferol-3-O-(2′′,3′′-di-O-acetyl)-α-L-rhamnopyranoside, kaempferol-3-O-(3′′,4′′-di-O-acetyl)-α-L-rhamnopyranoside, kaempferol-3-O-(4′′-Oacetyl)-α-L-rhamnopyranoside, kaempferol, and kaempferol-3-O-(2′′,4′′-di-O-acetyl)-α-L-rhamnopyranoside showed that these flavonoids exhibited remarkable anti-bacterial activities with a MIC values between 62.50 μg/mL and 500 μg/mL against E. coli, K. pneumoniae, S. aureus, and B. cereus [36]. In another study, luteolin, 3,5-dihydroxy-6,7,8,4′tetramethoxyflavone, apigenin, 3,5-dihydroxy-6,7,8-trimethoxyflavone, apigenin 7-O-glucoside, apigenin 4′-O-glucoside, kaempferol 3-O-glucoside, luteolin 4′-O-glucoside, luteolin 4′,7-O-diglucoside, kaempferol, kaempferol 7-O-glucoside, and quercetin 3-O-glucoside were reported for their vast anti-microbial activities against P. aeruginosa [38]. Apigenin and isoflavones exhibited anti-bacterial activity [16]. Genistein, kaempferol, naringenin, and catechin isolated from Brassica oleracea var. Capitata L. possessed anti-bacterial activity against E. coli and S. aureus [52].
The flavonoids, 3-hydroxy flavone derivatives, and 3-methyl flavanone showed activity against Gram +ve bacteria [75]. Scandenone, kaempferol-3,7-O-α-L-dirhamnoside tiliroside, quercetin-3,7-O-α-L-dirhamnoside showed anti-microbial activity [43]. 7-Methoxy-3, 3′,4′,6-tetrahydroxyflavone, 3,3′,4′,7-tetrahydroxyflavone (fisetin ), naringenin, 2′,7-dihydroxy-4′,5′-dimethoxyisoflavon, 3′-hydroxydaidzein and xenognosin B exhibited the anti-bacterial activities against B. subtili ATCC 6633, S. aureus ATCC25932, and B. cereus ATCC7064 [48]. The 2′,4′-dihydroxy-4methoxy-3′-prenyldihydrochalcone, 4-hydroxyonchocarpin, isobavachalcone, 2′,4′-dihydroxy-3,4-(2′′,2′′dimethylchromeno)-3′-prenyldihydrochalcone, 5,7-dihydroxy4′-methoxy-6-prenylflavanone, 5-hydroxy-6,7-(2,2dimethylchromano)-4′-methoxyflavanone, 4′,5-dihydroxy-6,7(2,2-dimethylchromeno)-2′-methoxy-8-γ,γ-dimethylallylflavone, artocarpin, pyranocycloartobiloxanthone A, and cycloheterophyllin isolated from Artocarpus lowii King and Artocarpus anisophyllus Miq showed activity against S. aureus, P. putida, B. cereus, E. coli, C. albicans, and C. glabrata [49].
4.4 Anti-cancer activity
The term cancer refers to a disease in which cells of a tissue undergo uncontrolled and often rapid proliferation [85]. This is also the loss of control of growth [86]. Alternative medicine has been used to treat cancer [87] and flavonoids, especially from plant sources, have not been left out. The pharmacological properties of flavonoids have made them useful alternatives to inhibit cell damage [73]. Flavonoids have been reported to be good anti-cancer therapeutics [88]. Quercetin particularly has been reported to be effective in the treatment of stomach, lung, prostate, and breast cancers [29]. Pradhan et al. 2015 reported the anti-tumor activity of quercetin without toxicity on the breast cancer cell, MCF-7 [89]. The anti-cancer activity of quercetin has been linked to the inhibition of the enzyme (DNA gyrase) [90]. Luteolin isolated from the leaves of Struchium sparganophora has caused cell death of melanoma and ovarian cancer cell lines [51]. Luteolin-7-O-β-glucopyranoside, formononetin-7-O-β-D-glucoside, and quercetin-3-O-β-d-glucuronide isolated from the leaves of Cassia tora linn were active against breast cancer (MCF7) [53]. Luteolin from the Vitex negundo Lin was an active anti-tumor agent [55]. In another study, the 2′, 5-dihydroxy-7-methoxyflavanone and 2′, 5-dihydroxy-7-methoxyflavone isolated from Andrographis glandulosa were active against HeLa, MIA PaCa, and U-8 [56]. Quercetin has been reported to induce cytotoxicity in cancer cells [91]. Kaempferol isolated from Ageratum conyzoides L. exhibited activity against lung cancer, gastric cancer, colon cancer, and glioma cancer [57]. Pinostrobin isolated from Cajanus cojan exhibited anti-leukemia activity [58]. The cynaroside isolated from H. chillensis was active against OVACAR-8, HCT-116, and SF-295 [59]. Nobiletin at 20 μM inhibited human ovarian cancer [76].
Quercetin, kaempferol, myricetin, luteolin, and apigenin isolated from the aqueous and/or alcohol extracts of Khlu leaves exhibited anti-cancer activities [34]. Quercetin has shown anti-tumor activity [25]. Myricetin and quercetin inhibited mammalian TrxRs with IC50 values of 0.62 and 0.97 Mmol/L, respectively [92]. Apigenin has been reported to arrest HT29 colon cancer [50]. Oncamex showed a strong anti-tumor effect against breast cancer while hesperetin was active against lung and carcinoma cancer cells [93]. Hesperidin and naringin isolated from the alcoholic extract of Colvillea racemosa were active against colon carcinoma cell lines (HCT-116) [40]. Quercitin, morin, and myricetin have shown protective effects in the prevention of liver, cardiovascular diseases, and cancer [16].
4.5 Anti-inflammatory
Inflammation is a normal biological process in response to pathogen infection, tissue injury, or chemical irritation [16]. The anti-inflammatory properties of anthocyanins have been reported [81]. Previous in vitro studies of flavonoids showed inhibition against LPS-induced TNF-α production [94]. The report of the phytochemical investigation of Vicia sativa led to the isolation of apigenin 4′-Oβ-D-glucopyranoside, isoquercetin, nicotiflorin, and apigenin 6-Cα-L-arabinopyranoside-8-Cβ-D-glucopyranoside that showed significant anti-edematogenic activity (P < 0.05) [66]. Isorhamnetin 3-O-b-D-glucoside, cirsiliol, chrysosplenol D, and artemetin isolated from Chrysanthemum morifolim Ramat inhibited the NO production in LPS-induced RAW 264.7 cells [67]. Daidzein, quercetin, genistein, and kaempferol have inhibited the production of both STAT-1 and NF-κB [95]. Similarly, the 3-methoxy quercetin isolated from Garcinia kola Heckel at concentrations (25 and 125 μM) inhibited the production of TNF-α [69]. The quercetin 3-O-훼-L-arabinopyranosyl(1→2)-훼-L-rhamnopyranoside isolated from Kalanchoe pinnata (Lamarck) Persoon showed anti-inflammatory activity [70]. At higher doses, flavonoids have shown a decrease in proliferation, CD14 surface marker, and NO production [96]. The flavonoids, artocarpanone A, artocarpanone, and heteroflavanones B and C have shown a remarkable inhibitory effect on iNOS protein expression and NO production in RAW 264.7 cells [97].
4.6 Anti-fungal activity
The flavonoids, diglycosylflavones, flavonol-3-O-glycosides, and proanthocyanidins isolated from Ephedra alata showed anti-fungal activity [22], nobiletin and langeritin, and hesperidin exhibited strong and weak anti-fungal activities, respectively [2]. The flavonoid, baicalein, showed anti-candidal activity against C. tropicalis 170.06, C. albicans ATCC 64550, and C. parapsilosis 153.07 with the MIC50 of 2.6, 26, and 13 μg ml−1, respectively [98]. The 3,5-dihydroxy-7-methoxy anthocynidines isolated from Monanthotaxis littoralis was active against mycotoxigenic [71]. (-)-epicatechin-3-Ob-glucopyranoside, 6-p-hydroxybenzyltaxifolin-7-O-b-D-glucoside, 5-hydroxy-3-(4-hydroxylphenyl) pyrano[3,2-g]chromene-4(8H)-one (-)-epicatechin(2(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol, and quercetin-3-O-a-glucopyranosyl-(1 2)-b-D-glucopyranoside isolated from Mangifera indica L exhibited anti-fungal activity [99].
4.7 Anti-ulcer activity
An ulcer is a disease of the alimentary tract caused by an inflamed break in the mucus lining membrane [100]. The anti-ulcer activity of quercetin in animals has been reported [72]. The phytochemical investigation of the aqueous extract of Ximenia americana led to the isolation of procyanidins B and C as well as catechin/epicatechin which were active against acute gastric ulcer [60]. The spinacetin 3-O-[α-L-rhamnopyranosyl-(1→6)-βD-glucopyranoside]-7-O-[α-L-rhamnopyranoside], kaempferol-3-Orutinoside, kaempferol-7-O-β-D-glucopyranoside, and quercetin-7-O-β-D-glucopyranoside isolated from the ethanol extracts of Anvillea garcinii showed a powerful anti-ulcer [64]. The hesperidin isolated from Citrus sinensis showed anti-ulcer activity [65].
4.8 Anti-edematogenic activity
Catechin, rutin, quercitrin, quercetin, and kaempferol isolated from the H2O 100% EtOH (1:1) of Ximenia americana L showed anti-edematogenic activity against ear edema in rat [63]. Artemetin isolated from Cordia curassavica DC exhibited remarkable anti-edematogenic activity [68].
5 Conclusions
Twenty-two members of the different families containing flavonoids studied for their health benefits confirmed the medicinal importance of these phytochemicals from these sources. The pharmacological pieces of evidence reported in the literature has proven that these flavonoids have shown anti-cancer, anti-microbial, anti-oxidant, anti-inflammatory, anti-fungal, anti-ulcer, and anti-edematogenic activity. Out of the references cited, 30% focused on the anti-oxidant activity of flavonoids, key in protecting the body against free radicals and oxidative stress. Also, 18% of the references showed anti-microbial and anti-cancer activities. Further literature reports indicated that flavonoids from these families exhibited anti-inflammatory and anti-edematogenic (9%), anti-viral and anti-ulcer (5%), anti-fungal, anti-nociceptive, and anti-histaminice (2%). The pharmacological activities of flavonoids from the various sources reviewed in this study show that the secondary metabolites could provide a scaffold for the development of potent anti-cancer drugs in the future.
Availability of data and materials
The search was by using keywords such as flavonoids. Other sources used are “science direct,” “google scholar,” “Scopus” database and many journal sites. Journals employed in the search are Elsevier and Springer. Other search engines used as well as papers published between 2006 and 2019.
Abbreviations
- MPLC:
-
Medium pressure liquid chromatography
- LC-ESI/MS:
-
Liquid chromatography electrospray ionization mass spectrometry
- TLC:
-
Thin layer chromatography
- VLC:
-
Vacuum liquid chromatography
- LC-MS:
-
Liquid chromatography-mass spectrometry
- HPLC-MS:
-
High-performance liquid chromatography-mass spectrometry
- EIMS:
-
Electrospray ionization mass spectrometry
- HPLC-DAD:
-
High-performance liquid chromatography with diode array detection
- GC-MS:
-
Gas chromatography-mass spectrometry
References
Sangeetha KSS, Umamaheswari S, Reddy CUM, Kalkura SN (2016) Flavonoids: Therapeutic potential of natural pharmacological agents. Int J Pharm Sci Res 7(10):3924–3930. https://doi.org/10.13040/IJPSR.0975-8232
Tapas A, Sakarkar D, Kakde R (2008) Flavonoids as Nutraceuticals: A Review. Trop J Pharm Res 7(3):1089–1099. https://doi.org/10.4314/tjpr.v7i3.14693
Datta N, Singanusong R, Chen SS, Yao LH, Jiang YM, Shi J, Tomás‐Barberán FA (2004) Flavonoids in Food and Their Health Benefits. Plant Foods Hum Nutr 59:113–122
Rudrapal M, Chetia D (2016) Plant flavonoids as potential source of future antimalarial leads. Syst Rev Pharm 8(1):13–18. https://doi.org/10.5530/srp.2017.1.4
Kozłowska A, Szostak-Wegierek D (2014) Flavonoids—food sources and health benefits. Rocz Panstw Zakl Hig 65(2):79–85
Weston LA, Mathesius U (2013) Flavonoids: their structure, biosynthesis and role in the rhizosphere, including allelopathy. J Chem Ecol 39:283–297. https://doi.org/10.1007/s10886-013-0248-5
Górniak I, Bartoszewski R, Króliczewski J (2019) Comprehensive review of antimicrobial activities of plant flavonoids. Phytochem Rev 18:241–272
Alzand KI, Mohamed MA (2012) Flavonoids: Chemistry, Biochemistry and Antioxidant activity. J Pharm Res 5(8):4013–4020
Lakhanpal P, Rai DK (2007) Quercetin: A Versatile Flavonoid. Int J Med Update 2(2):22–37. https://doi.org/10.4314/ijmu.v2i2.39851
Sumira J, Abbas N (2013) Chemistry of Himalayan Phytochemicals. Stud Nat Prod Chem:1–15
Karak P (2019) Biological activities of flavonoids: an overview. Int J Pharm Sci Res 10(4):1567–1574. https://doi.org/10.13040/IJPSR.0975-8232
Venkateswara RP, Kiran SDVS, Rohini P, Bhagyasree P (2017) Flavonoid: a review on naringenin. J Pharmacogn Phytochem 6(5):2778–2783
Jaiswal N (2013) Protective effect of flavonoids in multiple sclerosis. J Sci Innov Res 2(3):509–511
Sülsen VP, Lizarraga E, Mamadalieva NZ, Lago JHG (2017) Potential of Terpenoids and Flavonoids from Asteraceae as Anti-Inflammatory, Antitumor, and Antiparasitic Agents. Evid Based Complement Altern Med 2017:6–8. https://doi.org/10.1155/2017/6196198
Egert S, Rimbach G (2011) Which sources of flavonoids: complex diets or dietary supplements? Am Soc Nutr Adv Nutr 2:8–14. https://doi.org/10.3945/an.110.000026.8
Tiwari CS, Husain N (2017) Biological activities and role of flavonoids in human health – a review. Indian J Sci Res 12(2):193–196
Saxena M, Saxena J, Pradhan A (2012) Flavonoids and phenolic acids as antioxidants in plants and human health. Int J Pharm Sci Rev Res 16(2):130–134
Ozcan T, Delikanli B, Yilmaz-Ersan L, Akpinar-Bayizit A (2014) Phenolics in human health. Int J Chem Eng Appl 5(5):393–396. https://doi.org/10.7763/IJCEA.2014.V5.416
Lin G, Chan SSK, Chung HS, Li SL (2005) Chemistry and biological activities of naturally occurring phthalides. Stud Nat Prod Chem 32:611–669. https://doi.org/10.1016/S1572-5995(05)80065-1
Heim KE, Tagliaferro AR, Bobilya DJ (2002) Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13:572–584. https://doi.org/10.1016/S0955-2863(02)00208-5
Lumbiny BJ, Hui Z, Islam MA (2014) Antiaging, antioxidant flavonoids; synthesis, antimicrobial screening as well as 3D QSAR CoMFA models for the prediction of biological activity. J Asiat Soc Bangladesh Sci 39(2):191–199. https://doi.org/10.3329/jasbs.v39i2.17856
Chebouat E, Dadamoussa B, Gharabli S, Gherraf N, Allaoui M, Cheriti A, Lahham A, Zellagui A (2014) Assessment of antimicrobial activity of flavonoids extract from Ephedra alata. Der Pharm Lett 6(3):27–30
Hayat M, Abbas M, Munir F, Hayat MQ, Keyani R, Amir R (2017) Potential of plant flavonoids in pharmaceutics and nutraceutics. J Biomol Biochem 1(1):12–17
Singh NK, Rani M, Sharmila RT, Yadav AK (2017) Flavonoids in rice, their role in health benefits. MOJ Food Process Technol 4(3):96–99. https://doi.org/10.15406/mojfpt.2017.04.00095
Kumar R, Vijayalakshmi S, Nadanasabapathi S (2017) Health Benefits of Quercetin. Def Life Sci J 2(2):142. https://doi.org/10.14429/dlsj.2.11359
Amić D, Davidović-Amić D, Drago B, Trinajstić N (2003) Structure-radical scavenging activity relationships of flavonoids dragan. Croat Chem Acta 76(1):55–61
Dewick PM (1998) Medicinal natural products: a biosynthetic approach, 1st edn. Wiley, pp 135–137
American Institute for Cancer Research (2015) Flavonoids in your foods: here’s where to get them. www.aicr.org/wp-content/up
Awouafack MD, Tane P, Morita H (2017) Isolation and structure characterization of flavonoids. Intech open:45–59
Hostettmann K, Hostettmann M (1982) Isolation techniques for flavonoids. Flavonoids Springer Sci:1–18
Lobo RO, Dias FO, Shenoy CK (2017) Kombucha for healthy living: Evaluation of antioxidant potential and bioactive compounds. Int Food Res J 24(4):541–546
Karasakal A, Demirci AS, Demirok NT, Cabi E (2015) Antioxidant, antimicrobial activities and total flavonoid contents of Cirsium bulgaricum DC. leaf extracts. Marmara Pharm J 19:43–51. https://doi.org/10.12991/mpj.2015198609
Iskender H, Yenice G, Dokumacioglu E, Kaynar O, Hayirli A, Kaya A (2016) The effects of dietary flavonoid supplementation on the antioxidant status of laying hens. Brazilian Journal of Poultry Science 18(4):663–668. https://doi.org/10.1590/1806-9061-2016-0356
Suriyaphan O (2014) Nutrition, health benefits and applications of Pluchea indica (L.) less leaves. Mahidol Univ J Pharm Sci 41(4):1–10
Traithip A (2005) Phytochemistry and Antioxidant Activity of Pluchea Indica, pp 4–6
Sivasothy Y, Sulaiman SF, Ooi KL, Ibrahim H, Awang K (2013) Antioxidant and antibacterial activities of flavonoids and curcuminoids from Zingiber spectabile Griff. Food Control 30:714–720. https://doi.org/10.1016/j.foodcont.2012.09.012
Van Der Sluis AA, Dekker M, Jongen WMF, De Jager A (2003) Polyphenolic antioxidants in apples. Effect of storage conditions on four cultivars. Acta Hortic 600:533–540. https://doi.org/10.17660/ActaHortic.2003.600.80
Süzgeç-Selçuk S, Birteksöz AS (2011) Flavonoids of Helichrysum chasmolycicum and its antioxidant and antimicrobial activities. South African J Bot 77:170–174. https://doi.org/10.1016/j.sajb.2010.07.017
Rattanachaikunsopon P, Phumkhachorn P (2010) Contents and antibacterial activity of flavonoids extracted from leaves of Psidium guajava. J Med Plant Res 4(5):393–396
Shafei AA (2016) Qualitative and quantitative estimation of flavonoids and phenolic compounds and the biological activities of Colvillea racemosa cultivated in Egypt. Int J Pharmacogn Phytochem Res 8(5):836–840
Ngoc PTK, Nguyet NTM, Dao DTA (2017) Antimicrobial and antioxidant properties of the flavonoid extract from Raphanus sativus L. AIP Conf Proc 1878:020026. https://doi.org/10.1063/1.5000194
Özçelik B, Orhan DD, Özgen S, Ergun F (2008) Antimicrobial Activity of Flavonoids against Extended-Spectrum β-Lactamase (ESβL)-Producing Klebsiella pneumoniae. Trop J Pharm Res 7(4):1151–1157. https://doi.org/10.4314/tjpr.v7i4.14701
Özçelik B, Orhan I, Toker G (2006) Antiviral and antimicrobial assessment of some selected flavonoids. Zeitschrift fur Naturforsch - Sect C J Biosci 61:632–638
Zahoor M, Shafiq S, Ullah H, Sadiq A, Ullah F (2018) Isolation of quercetin and mandelic acid from Aesculus indica fruit and their biological activities. BMC Biochem 19:1–14
Geçibesler HI (2017) In Vitro Biological Activity Studies on Tanacetum abrotanifolium (L.) Druce (Asteraceae). Anadolu Univ J Sci Technol A-Appl Sci Eng 18(2):439–455. https://doi.org/10.18038/aubtda.284496
Sharma Y, Nagar A, Srivastava NS, Bala K (2017) Antioxidant activity of polyphenolic flavonoid of stem of Nicotiana tabacum. Am J Drug Discov Dev 7(1):25–32. https://doi.org/10.3923/ajdd.2017.25.32
Fukuda M, Ohkoshi E, Makino M, Fujimoto Y (2006) Studies on the constituents of the leaves of Baccharis dracunculifolia (Asteraceae) and their cytotoxic activity. Chem Pharm Bull 54:1465–1468. https://doi.org/10.1248/cpb.54.1465
Taechowisan T, Chanaphat S, Ruensamran W, Phutdhawong WS (2014) Antibacterial activity of new flavonoids from Streptomyces sp. BT01; an endophyte in Boesenbergia rotunda (L.) mansf. J Appl Pharm Sci 4(4):8–13. https://doi.org/10.7324/JAPS.2014.40402
Jamil S, Lathiff SMA, Abdullah SA, Jemaon N, Sirat HM (2014) Antimicrobial flavonoids from Artocarpus Anisophyllus miq. and artocarpus lowii King. J Teknol 71(1):95–99. https://doi.org/10.11113/jt.v71.2699
Sajjadi SE, Ghanadian M, Haghighi M (2016) Isolation and identification of two phenolic compounds from a moderately cytotoxic fraction of Cousinia verbascifolia Bunge. Adv Biomed Res 6:1–5. https://doi.org/10.4103/2277-9175.190980
Kasim LS, Ferro V, Odukoya OA, Ukpo GE, Seidel V, Gray AI, Waigh R (2011) Cytotoxicity of isolated compounds from the extracts of Struchium sparganophora (Linn) Ktze asteraceae. Pak J Pharm Sci 24(4):475–478
Satish A, Farha SS, Urooj A (2018) Quantification of flavonoids by UPLC-MS and its antibacterial activity from Brassica oleracea var. Capitata L. GSC Biol Pharm Sci 5(1):109–114
Vijayalakshmi A, Masilamani K, Nagarajan E, Ravichandiran V (2015) In vitro antioxidant and anticancer activity of flavonoids from Cassia Tora linn. leaves against human breast carcinoma cell lines. Der Pharma Chem 7(9):122–129
Ahmed SI, Hayat MQ, Tahir M, Mansoor Q, Ismail M, Keck K, Bates RB (2016) Pharmacologically active flavonoids from the anticancer, antioxidant and antimicrobial extracts of Cassia angustifolia Vahl. BMC Complement Altern Med 16:1–9. https://doi.org/10.1186/s12906-016-1443-z
Chowdhury AR, Sharma S, Mandal S, Goswami A, Mukhopadhyay S, Majumder HK (2002) Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J 366:653–661. https://doi.org/10.1042/BJ20020098
Cherukupalli N, Bhumireddy SR, Akella SSV, Sataniya A, Sripadi P, Khareedu VR, Vudem DR (2017) Phytochemical profiling and in vitro anticancer activity of purified flavonoids of Andrographis glandulosa. Planta Medica Int Open 4:24–34. https://doi.org/10.1055/s-0043-105274
Tan NH, Akindahunsi AA, Zeng GZ, Zhang YM, Adebayo AH (2010) Anticancer and antiradical scavenging activity of Ageratum conyzoides L. (Asteraceae). Pharmacogn Mag 6(21):62. https://doi.org/10.4103/0973-1296.59968
Ashidi JS, Houghton PJ, Hylands PJ, Efferth T (2010) Ethnobotanical survey and cytotoxicity testing of plants of South-western Nigeria used to treat cancer, with isolation of cytotoxic constituents from Cajanus cajan Millsp. leaves. J Ethnopharmacol 128:501–512. https://doi.org/10.1016/j.jep.2010.01.009
da Silva ACN, do Nascimento RMC, do Nascimento RDC, Ferreira PMP, Pessoa C, Lima DJB, de Moraes Filho MOF, de Almeida RM, Ferreira SR, Fujiwara RT, do Nascimento AM (2019) In vitro activity evaluation of seven Brazilian Asteraceae against cancer cells and Leishmania amazonensis. South African J Bot 121:267–273. https://doi.org/10.1016/j.sajb.2018.11.008
Aragão TP, dos Prazeres LDKT, Brito SA, PJR N, Rolim LA, da Silva AJRG, Caldas GFR, Wanderley AG (2018) Contribution of secondary metabolites to the gastroprotective effect of aqueous extract of ximenia americana L. (Olacaceae) stem bark in rats. Molecules 23:112. https://doi.org/10.3390/molecules23010112
Sánchez-Gutiérrez JA, Vázquez-Sánchez M, Álvarez-Bernal D, Mares-Quiñones MD, Valiente-Banuet JI, Medina-Medrano JR, Villar-Luna E (2018) Determination of phenolic compounds and the antioxidant capacity of Ximenia parviflora Benth. var. parviflora (Olacaceae) fruit by high-performance liquid chromatography with diode array detection. Anal Lett 51:1986–1998. https://doi.org/10.1080/00032719.2017.1404094
Simona Ioana Vicas DR and CS (2012) Antioxidant activity of European mistletoe (Viscum album), phytochemicals as nutraceuticals - global approaches to their role in nutrition and health,115-134
da Silva BAF, da Costa RHS, Fernandes CN, Leite LHI, Ribeiro-Filho J, Garcia TR, Coutinho HDM, Wanderley AG, de Menezes IRA (2018) HPLC profile and antiedematogenic activity of Ximenia americana L. (Olacaceae) in mice models of skin inflammation. Food Chem Toxicol 119:199–205. https://doi.org/10.1016/j.fct.2018.04.041
Perveen S, Fawzy GA, Al-Taweel MA, Orfali RS, Yusufoglu HS, Abdel-Kader MS, Al-Sabbagh RM (2018) Antiulcer activity of different extracts of Anvillea garcinii and isolation of two new secondary metabolites. Open Chem 16:437–445
Bigoniya P, Singh K (2014) Original article ulcer protective potential of standardized hesperidin, a citrus flavonoid isolated from Citrus sinensis. Brazilian J Pharmacogn 24:330–340
Gamal-Eldeen AM, Kawashty SA, Ibrahim LF, Shabana MM, El-Negoumy SI (2004) Evaluation of antioxidant, anti-inflammatory, and antinociceptive properties of aerial parts of Vicia sativa and its flavonoids. J Nat Remedies 4(1):81–96
Hu J, Ma W, Li N, Wang K (2017) Antioxidant and anti-inflammatory flavonoids from the flowers of Chuju, a medical cultivar of Chrysanthemum Morifolim Ramat. J Mex Chem Soc 61(4):282–289
Bayeux MC, Fernandes AT, Foglio MA, Carvalho JE (2002) Evaluation of the antiedematogenic activity of artemetin isolated from Cordia curassavica DC. Braz J Med Biol Res 35(10):1229–1232
Omeje EO, Nworu SC, Osadebe PO, Onugwu L, Maurya R, Okafor SN, Proksch P (2017) In- vitro anti-inflammatory activities of 3-methoxy quercetin isolated from Nigerian mistletoe parasitic on Garcinia kola Heckel, Clusiaceae. Trop J Pharm Res 16(5):1059–1067. https://doi.org/10.4314/tjpr.v16i5.13
Ferreira RT, Coutinho MAS, Malvar DC, Costa EA, Florentino IF, Costa SS, Vanderlinde FA (2014) Mechanisms underlying the antinociceptive, antiedematogenic, and anti-inflammatory activity of the main flavonoid from Kalanchoe pinnata. Evidence-Based Complement Altern Med 2014:1–8. https://doi.org/10.1155/2014/429256
Clara C, Matasyoh JC, Wagara IN, Nakavuma J (2014) Antifungal activity of flavonoids isolated from Monanthotaxis littoralis against mycotoxigenic fungi from maize. Am J Chem Appl 1(4):54–60
Rana AC, Gulliya B (2019) Chemistry and pharmacology of flavonoids- a review. Indian J Pharm Educ Res 53(1):130–134. https://doi.org/10.5530/ijper.53.1.3
Ruiz-Cruz S, Chaparro-Hernández S, Hernández-Ruiz KL, Cira-Chávez LA, Estrada-Alvarado MI, Gassos Ortega LE, José de Jesús Ornelas-Paz J, MAL M Flavonoids: Important Biocompounds in Food. Intech Open:354–369. https://doi.org/10.5772/67864
Procházková D, Boušová I, Wilhelmová N (2011) Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 82:513–523. https://doi.org/10.1016/j.fitote.2011.01.018
Kamlesh KN, Sivakumar T, Afroze A (2017) Antimicrobial Activity of Flavone Analogues. J Appl Pharmacol 9(1):1–9. https://doi.org/10.21065/1920-4159.1000232
Sandu M, Bîrsă LM, Bahrin LG (2017) Flavonoids – Small Molecules, High Hopes. Acta Chem Iasi 25(1):6–23. https://doi.org/10.1515/achi-2017-0003
Majewska M, Skrzycki M, Podsiad M, Czeczot H (2011) Evaluation of antioxidant potential of flavonoids: An in vitro study. Acta Pol Pharm-Drug Res 68(4):611–615
Kumar S, Pandey AK (2013) Chemistry and Biological Activities of Flavonoids: An Overview. Sci World J:1–16. https://doi.org/10.1155/2013/162750
Russo D (2018) Pharmacognosy & Natural products flavonoids and the structure-antioxidant activity relationship. J Pharmacogn Nat Prod 4(1):30–31. https://doi.org/10.4172/2472-0992.1000e109
Martinez-Perez C, Ward C, Cook G, Mullen P, McPhail D, Harrison DJ, Langdon SP (2014) Novel flavonoids as anti-cancer agents: mechanisms of action and promise for their potential application in breast cancer. Biochem Soc Trans 42(4):1017–1023. https://doi.org/10.1042/BST20140073
Khan MAY, Mundasada SC, Ramadas D (2015) Antioxidant activity : root, leaves and fruits aqueous extracts of Muntingia Calabura. J Innov Pharm Biol Sci 2(4):363–368
Wafa N, Sofiane G, Mouhamed K (2016) The antioxidant and antimicrobial activities of flavonoids and tannins extracted from Phlomis bovei De Noé. Eur J Exp Biol 6(3):55–61
Nishigaki I, Peramaiyan R, Ramachandran V, Gnapathy E, Dhanapal S, Yutaka N (2010) Cytoprotective role of astaxanthin against glycated protein/iron chelate-induced toxicity in human umbilical vein endothelial cells. Phyther Res 24(9):54–59. https://doi.org/10.1002/ptr
Khanna A, Maurya PK (2012) Role of tea catechins in prevention of aging and age-related disorders. Tang [Humanitas Med] 2(1):2.1–2.11. https://doi.org/10.5667/tang.2011.0016
Pawar SR, Jangam S, Waghmare S (2018) Anti-cancer herbal drugs: an overview. J Drug Deliv Ther 8(4):48–58
Elnour AM, Penech F, Mesaik AM (2018) Four selected sudanese medicinal plants induce anticancer and cytotoxic effects in prostate cancer cell line. Clin Med Biochem 3(2):3–6. https://doi.org/10.4172/2471-2663.1000134
Roy A, Ahuja S, Bharadvaja N (2017) A review on medicinal plants against cancer anticancer activity of medicinal plants. J Plant Sci Agric Res 2(1):1–5
Ragazzon PA, Iley J, Missailidis S (2009) Structure-activity studies of the binding of the flavonoid scaffold to DNA. Anticancer Res 29:2285–2293
Pradhan D, Pradhan RK, Tripathy G, Pradhan S (2015) Inhibition of proteasome activity by the dietary flavonoid Quercetin associated with growth inhibition in cultured breast cancer cells and xenografts. J Young Pharm 7(3):225–233. https://doi.org/10.5530/jyp.2015.3.13
Cushnie TPT, Lamb AJ (2005) Antimicrobial activity of flavonoids. Int J Antimicrob Agents 26:343–356. https://doi.org/10.1016/j.ijantimicag.2005.09.002
Srivastava S, Somasagara RR, Hegde M, Nishana M, Tadi SK, Srivastava M, Choudhary B, Raghavan SC (2016) Quercetin, a natural flavonoid interacts with DNA, arrests cell cycle and causes tumor regression by activating mitochondrial pathway of apoptosis. Sci Rep 6:1–13. https://doi.org/10.1038/srep24049
Lu J, Papp LV, Fang J, Rodriguez-Nieto S, Zhivotovsky B, Holmgren A (2006) Inhibition of mammalian thioredoxin reductase by some flavonoids: Implications for myricetin and quercetin anticancer activity. Cancer Res 66(8):4410–4418. https://doi.org/10.1158/0008-5472.CAN-05-3310
Stanisic D, Costa FA, Favaro FW, Tasic L, Seabra AB, Duran N (2018) Anticancer activities of hesperidin and hesperetin in vivo and their potentiality against bladder cancer. J Nanomed Nanotechnol 9(5). https://doi.org/10.4172/2157-7439.1000515
Ueda H, Yamazaki C, Yamazaki M (2004) A hydroxyl group of flavonoids affects oral anti-inflammatory activity and inhibition of systemic tumor necrosis factor- α production. Biosci Biotechnol Biochem 68(1):119–125. https://doi.org/10.1271/bbb.68.119
Nieminen R, Vuorela P, Heinonen M, Moilanen E (2007) Anti-inflammatory effects of flavonoids : genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF- κ B activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κB activation along with their inhibitory. Mediat Inflamm 2007:1–10. https://doi.org/10.1155/2007/45673
Gupta A, Chaphalkar SR (2016) Anti-inflammatory and immunosuppressive activities of flavonoids from medicinal plants. J Herb Med Pharmacol 5(3):120–124
Bai-Luh W, Jing-Ru W, Pao-Hui C, Chi-Feng H, Jih-Pyang W, Lin C (2005) Antiinflammatory Flavonoids from Artocarpus heterophyllus and Artocarpus communis. J Agric Food Chem 53:3867–3871
Serpa R, Franc EJG, Furlaneto-maia L, Andrade CGTJ, Diniz A, Furlaneto MC (2012) In vitro antifungal activity of the flavonoid baicalein against Candida species. J Med Microbiol 61:1704–1708. https://doi.org/10.1099/jmm.0.047852-0
Kanwala Q, Hussain I, Siddiqui HL, Javaid A (2010) Antifungal activity of flavonoids isolated from mango (Mangifera indica L.) leaves. Nat Prod Res 24(20):1907–1914. https://doi.org/10.1080/14786419.2010.488628
Vimala G, Shoba FG (2014) A review on antiulcer activity of few indian medicinal plants. Int J Microbiol 2014:1–14
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Ekalu, A., Habila, J.D. Flavonoids: isolation, characterization, and health benefits. Beni-Suef Univ J Basic Appl Sci 9, 45 (2020). https://doi.org/10.1186/s43088-020-00065-9
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DOI: https://doi.org/10.1186/s43088-020-00065-9