molecules Review Important Flavonoids and Their Role as a Therapeutic Agent Asad Ullah 1 , Sidra Munir 1 , Syed Lal Badshah 1,* , Noreen Khan 1, Lubna Ghani 2, Benjamin Gabriel Poulson 3 , Abdul-Hamid Emwas 4 and Mariusz Jaremko 3,* 1 Department of Chemistry, Islamia College University Peshawar, Peshawar 25120, Pakistan; [email protected] (A.U.); [email protected] (S.M.); [email protected] (N.K.) 2 Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, Azad Kashmir 13230, Pakistan; [email protected] 3 Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia; [email protected] 4 Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia; [email protected] * Correspondence: [email protected] (S.L.B.); [email protected] (M.J.) Received: 20 September 2020; Accepted: 1 November 2020; Published: 11 November 2020 Abstract: Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health. Keywords: flavonoids; polyphenols; quercetin; antioxidative; neuroprotective 1. Introduction Flavonoids are secondary metabolites, which mainly consists of a benzopyrone ring bearing a phenolic or poly-phenolic groups at different positions [1]. They are most commonly found in fruits, herbs, stems, cereals, nuts, vegetables, flowers and seeds [2,3]. The presence of bioactive phytochemical constituents present in these different plants parts gives them their medicinal value and biological activities [4]. So far, over 10,000 flavonoid compounds have been isolated and identified [5]. Most of the flavonoids are widely accepted as therapeutic agents [6]. These are naturally synthesized through the phenylpropanoid pathway with bioactivity dependent on its absorption mechanism and bioavailability [7]. Flavonoids have been used in natural dyes [8,9], in cosmetics and skin care products [10,11], and anti-wrinkle skin agents [12]. The most pronounced applications of these polyphenols, however, are in the field of medicine. Flavonoids have been used extensively as anticancer, [13] antimicrobial, antiviral, antiangiogenic [14,15], antimalarial, antioxidant, neuroprotective, antitumor, and anti-proliferative agents [16]. Apple peel extracts rich in flavonoids inhibits acetylcholinesterase (ACE) in vitro and is an effective antihypertensive agent [17–20]. It also prevents cardio-metabolic disorders [21] and displays better preservation of cognitive performance with aging [22]. Molecules 2020, 25, 5243; doi:10.3390/molecules25225243 www.mdpi.com/journal/molecules Molecules 2020, 25, 5243 2 of 39 Molecules 2020, 25, x FOR PEER REVIEW 2 of 39 vitro and is an effective antihypertensive agent [17–20]. It also prevents cardio-metabolic disorders They are classified into various types depending on their chemical structure, degree of unsaturation, [21] and displays better preservation of cognitive performance with aging [22]. and oxidation ofThey carbon are classified ring. Anthoxanthins into various types (flavanone depending and on flavanol), their chemical flavanones, structure, flavanonols, degree of flavans, chalchones,unsaturation, anthocyanidins, and oxidation and isoflavonoids of carbon ring. are Anthoxanthins the different (flavanone subgroups and flavanol), of flavonoids. flavanones, Each of these flavonoid isflavanonols widely distributed, flavans, chalchones, in nature anthocyanidins, (Figure1)[ and23]. isoflavonoid A highers intakeare the ofdifferent flavonoid subgroups rich of foods has a flavonoids. Each of these flavonoid is widely distributed in nature (Figure 1) [23]. A higher intake of number of health benefits [24]. Since these natural compounds have positive effects on human health, flavonoid rich foods has a number of health benefits [24]. Since these natural compounds have an increasingpositive eff orteffects has on beenhuman made health, toan increasing isolate these effort compoundshas been made to from isolate various these compounds plants. from For instance, citrus fruitsvarious are rich plants. sources For instance, of flavonoids. citrus fruits Twoare rich flavonoids, sources of flavonoids narigenin. Two and flavonoids, hesperetin, narigenin are found in oranges, lemons,and hesperetin, and grapes are found [25]. in Anthocyanins oranges, lemons, and and quercetin grapes [25 glycosides]. Anthocyanins flavonoids and quercetin are present in glycosides flavonoids are present in mulberry [26]. mulberry [26]. O Isoflavone O O O O OH OH O Flavonoid Flavonol Flavanol O O OH O Anthocyanin Flavonone FigureFigure 1. Chemical 1. Chemical structure structure of of flavonoidsflavonoids and and its different its different types. types. 2. Effects of2. Effects Flavonoids of Flavonoids on Human on Human Health Health 2.1. Anticancer Action 2.1. Anticancer Action Cancer is a major health problem caused by abnormal cell growth. There are various anticancer Cancerdrugs is a available, major health and yet problem only a few caused display byinhibition abnormal against cell oncogenesis, growth. and There a majority are various of them anticancer drugs available,are toxic and and have yet onlyadverse a fewside effects display [27] inhibition. Natural biomolecu againstlesoncogenesis, with secondary andmetabolites a majority have of them are toxic andphytomediated have adverse content, side and e ffdisplayects [ 27biological]. Natural activities biomolecules over a wide range with of secondary spectrum, laying metabolites the have basis for cancer prevention and treatment. Flavonoids are known to inhibit cell growth and act as an phytomediatedanticancer content, agents and[28,29 display]. Chemoprevention biological is activitiesthe use of natural overa or wide synthetic range substances of spectrum, to inhibit laying the basis for cancercarcinogenesis prevention [30]. Following and treatment. are copious Flavonoids examples of flavonoids are known and to their inhibit use as cell anticancer growth agents. and act as an anticancer agentsHesperedin [28,29 ].(Hsp) Chemoprevention is an important flavonoid is the which use of displays natural efficient or synthetic anticancer substances activity [31]. to inhibit carcinogenesisPolylactic [30].-co Following-glycolic acid are (PLGA) copious nanoparticles examples were of flavonoidssynthesized and and loaded their with use asHsp anticancer to form agents. hesperidin nanoparticles (HspNPs) to determine its potential application as an anticancer agent Hesperedinagainst C6 (Hsp) glioma is cells. an importantThe encapsulated flavonoid Hsp exhibited which decreased displays in vitro effi cientcell viability anticancer against activitythe [31]. Polylactic-co-glycolicC6 glioma cell line, acid and (PLGA) the controlled nanoparticles release of Hsp were decreased synthesized the cytotoxicity and loadedof PLGA [ with32]. Hsp to form hesperidin nanoparticlesAurone, a benzo (HspNPs)-furanone, to is determine another flavonoid its potential that has been application extensively as used an anticancer as an anticancer agent against C6 gliomaagent cells. [33 The]. Various encapsulated analogues Hsp of aurone exhibited display decreased different mechanismsin vitro cell against viability cancer against cells because the C6 glioma there are many possible targets. These targets include cyclin dependent kinase, histone deacetylase, cell line, andthe theadenosine controlled receptor, release telomerase, of Hsp sirtuins, decreased and microtubules the cytotoxicity [33]. of PLGA [32]. Aurone, aQuercetin benzo-furanone, is a natural isflavonoid another present flavonoid in plants that and has in commonly been extensively consumed usedfoods assuch an as anticancer agent [33].berries, Various green analogues tea, and grains. of aurone It has been display used most di ffeffectivelyerent mechanisms for colorectal cancer. against Cell cancer cycle arrest, cells because there are manyincrease possible in apoptosis, targets. antioxidant These targetsreplication, include modulat cyclinion of dependent estrogen receptors, kinase, regulation histone deacetylase,of signaling pathways, inhibition of metastasis and angiogenesis are among various mechanisms the adenosineunderlying receptor, the chemo telomerase,-preventive sirtuins, effects of and quercetin microtubules in colorectal [33 cancer]. [34]. Luteolin, a natural Quercetinflavonoid isa with natural pro-apopt flavonoidotic activity present in hepatocellular in plants carcinoma and in (HCC) commonly cells, arrests consumed the cancer foods cell such as berries,