An ethnopharmacological review on the therapeutical properties of flavonoids and their mechanisms of actions: A comprehensive review based on up to date knowledge

Flavonoids -a class of low molecular weight secondary metabolites- are ubiquitous and cornucopia throughout the plant kingdom. Structurally, the main structure consists of C6-C3-C6 rings with different substitution patterns so that many sub-classes are obtained, for example: flavonols, flavonolignans, flavonoid glycosides, flavans, anthocyanidins, aurones, anthocyanidins, flavones, neoflavonoids, chalcones, isoflavones, flavones and flavanones. Flavonoids are evaluated to have drug like nature since they possess different therapeutic activities, and can act as cardioprotective, antiviral, antidiabetic, anti-inflammatory, antibacterial, anticancer, and also work against Alzheimer's disease and others. However, information on the relationship between their structure and biological activity is scarce. Therefore, the present review tries to summarize all the therapeutic activities of flavonoids, their mechanisms of action and the structure activity relationship.


Introduction
Recent studies suggest the rational development of more potent, less toxic compounds that can be used clinically to treat of patients suffering from chronic diseases that cause oxidative stress.
Phytochemicals are plant-based molecules that protect people from many chronic diseases. Flavonoids are one of the most exciting types of phenolic compounds. They are found in a wide variety of plants. Studies in the chemistry of natural products are very common in leaves, flower tissues, pollen and fruits. This phytocompound is also abundant in stem and bark, and represents an integral part of human healthy life style. Flavonoids are existed broadly in nature. Concerns about their extensive profitable bioactive benefits, including anti-inflammatory, antioxidant, anti-viral, antifungal, antibacterial, antihypertensive, cardioprotective, anti-ulcer, anti-diabetic, anti-Alzheimer, anti-depression, and anticancer effects have been receiving great attention and support by numerous studies. Till now, more than 9000 flavonoids have been reported, and their daily intake varies between 20 mg and 500 mg, mainly from dietary supplements including apples, grapes, berries, tea, tomatoes and onions.
Notably, despite their broad benefits and wide distribution, flavonoids have poor bioavailability, which can significantly influence their nutritional value. Besides, information on their pharmacokinetics is limited. How the problem can be fixed is far from being resolved. This review attempts to summarize all the data about structure and activity of flavonoids, with particular emphasis on their mechanism of action.

Potential against Alzheimer's disease
Flavonoids are reported to have strong therapeutic activity in the treatment of Alzheimer's disease and are considered future drug candidates. The report included in this comprehensive review suggests that the main mechanism of action in the treatment of Alzheimer's disease is decreased due to the production of Reactive Oxygen Species (ROS) and beta amyloid protein. About 127 flavonoids were tested for anti-Alzheimer's activity and showed acetyl and butylcholinesterase inhibitors were responsible for their activity.

Anti-Alzheimer mechanism of action
Flavonoids can reduce Aβ plaque either by increasing the activity of α-secretase or by inhibiting β-secretase activity. They can interfere with fibrillation, inhibit beta amyloid protein aggregation through metal chelating activity, increase cerebral vascular blood flow, decrease beta amyloid protein levels, or inhibit the factors involved in nerve damage, for example: ROS, Nitric Oxide (NO), beta amyloid protein, phosphorylation of tau and Acetyl Choline Esterase (AChE) as summarized in Fig. 3 and Table 1.

Structure activity relationship for anti-Alzheimer activity
Central Nervous System drugs require greater liposolubility that can be enhanced by non-polar fragments (ex: aliphatic rings, alkyls and halogen atoms) in the molecules. At the same time, topological polarity surface area can affect the cellular drug molecules penetration. Previous studies have shown that flavonoids contain lower topological polarity surface area and higher water-lipid partition coefficient that can bypass blood brain barrier with potential activity.
Xie et al. [284] examined the structural aspects of the AChE inhibitory potential of flavonoids and found that the OH group in the A ring [122] (Fale et al., 2012) and hydrogen bonding play a role in increasing affinity for AChE. AChE inhibition generally increases by flavones and flavonols. Whereas methoxylation, glycosylation and hydrogenation of the C 2 -C 3 double bond decrease (Fig. 4). AChE inhibition depends on conjunction site, flavonoid class and sugar moiety.

Potential against depression
Flavonoids have been reported to have antidepressant activity [25,124]. Updated reports suggest that apigenin exhibits antidepressant activity via dopaminergic mechanism [292], whilst luteolin reduces stress on endoplasmic reticulum [107]. Other studies indicate that icarin inhibits the NF-κB receptor and activation of the 3-inflammatory / caspase-1 / IL-1β axis in the hippocampus [153], whereas antidepressant activity of rutin is displayed by increasing monoamines in synaptic clefts (Nöldner and, 2002) (Fig. 5, Table 2).

Structure-activity relationship
In flavonoids, the position of the OH group on ring A affects the antidepressant activity where compounds with the OH group at the 2,4 positions show high activity well as the C-glucoside flavones [77]. It has been reported that the sequence of antidepressant activity of flavonoids as follow: flavones >flavonols >flavonoids glycosides >flavanonols [85].

Anti-depressant mechanism of action
The antidepression mechanism of flavonoids include a) restoring monoamine levels, b) increasing neural survival and maturation, c) increasing neurogensis and neuroplasticity, d) increasing BDNF, e) decreasing neurotransmitters reuptake through receptor interaction.

Flavonoids increase biogenic amines
Flavonoids can increase levels of the monoamine neurotransmitter in neuronal synaptosomes, which leads to a reduction in clinical symptoms of depression [303,304].

Inhibition of bioamine reuptake
Flavonoids can re-absorbe 5-HT prevention by decreasing the number of 5-HT receptors and by inhibiting catechic acid transmethylase activity using synaptosomes [299]. This effect in turn  Abou Baker Toxicology Reports 9 (2022)   induces the expression of neuroamine transmission in the brain [275]. 3. Effects of flavonoids on the neuroendocrine system Flavonoids can enhance 5-HT neurological function and the action of adenylate cyclase and neurotrophic factor 5-HT receptor mediated (Butterweck et al., 2000). The increase in phosphorylated BDNF and cAMP-response element binding protein (CREB) was caused by hippocampal nerve synthesis (Knorr et al., 2017). In addition, increase the hippocampal nerve synthesis and BDNF expression (An et al., 2011). Flavonoids also inhibit stress hormone levels and increase the expression of glucocorticoid receptors in the hippocampus and prevent PC12 nerve cell damage (Patil et al., 2014) as well as its ability for restoration of IL-6 and TNF-α in serum (Pan 2006).
Flavonoids can inhibit ACh and triphosadenine,and limit ATP and α-amino-3-OH-5-methanoic acid [36]. One possible associated mechanism includes restoration of the activity of COX-2 (Li et al., 2013a(Li et al., , 2013b. Additionally, flavonoids can decrease levels of corticosterone and adrenocorticotropic hormones and can regulate corticotropin-releasing factor mRNA expression because they can modulate the DNA binding activity of glucocorticoid and cAMP receptors as well as the phosphorylation of extracellular kinase signal in the hypothalamus region.

Antioxidant potential
Oxidative stress refers to the excessive production of free radicals and other highly active enzymes causing imbalance of intracellular antioxidant capacity, which lead to lipid peroxidation, protein denaturation, and DNA damage. Oxidative stress is one of the main signs of inflammation. However, prolonged oxidative stress can damage the surrounding molecules. Recent clinical studies have shown that oxidative stress plays a crucial role in the development of many dangerous diseases such as cardiovascular disease [218,282], Alzheimer [234,301,41], cancer [189,87,9], diabetes [18]. The antioxidant potential of flavonoids has been well described in many studies (Havsteen 2002) [210].

Mechanism of antioxidant action
The antioxidant capacities of flavonoids are much powerful than those of VitC and VitE [209] by the following mechanisms:(a)

D.H. Abou Baker
Mitigateoxidation caused by NO [262]. b) Metal chelating activity [70]. c) Inhibit oxidases [52]. d) Activate antioxidant enzymes [187]. e) Reduce α-tocopheryl radicals [89,92]. f) Scavenge of ROS [187]. g) Increase in antioxidant properties of low molecularantioxidants [288]. h) Increase in uric acid levels [157]. The antioxidant effects of flavonoids also include a) inhibiting ROS production, either by chelating the trace elements or by inhibiting enzymes involved in ROS production; b) and improving regulation and protection of antioxidants. Flavonoids also inhibit ROS production enzymes, including monooxygenase, mitochondrial succinic oxidase, glutathione S-transferase, and NADH oxidase. The antioxidant mechanisms of flavonoids are listed in Table 3.

Structure activity relationship for antioxidant activity
Flavonoids are known to have high antioxidant activity. Many studies have shown significant differences in the antioxidant activity of the different flavonoid subgroups due to the many substitution patterns in their structures. Other studies discussed the structural effect on the antioxidant activity of flavonoids (Sichel et al., 1991; Rice-Evans et al., 1997). From these studies, the three main structural targets are summarized as follows (Fig. 6): a) The 3'-and 4'-OH groups connected to the B-ring in an ortho position appear to stabilize their radical form. This site is believed to be responsible for metal chelation. b) The 2, 3 double bond on the C-ring plays a decisive role in junction with the 4-oxo group and facilitates the electronic delocalization of the B-ring. In addition, the ketol structure of 4-keto and 3-OH or 5-OH appears to be another chelation site for metals. c) OH groups attached to rings A and C at positions 3, 5, and 7 seem to increase the antioxidant capacity together with the 4-oxo groups.

Potential against inflammation
Inflammation is responsible for chronic systemic damage which can lead to many dangerous diseases. There is currently a growing   understanding of the effects of diet on inflammatory diseases. Therefore, the effects of flavonoids as an essential part of a healthy diet have received more attention because of their anti-inflammatory effects [90]. Flavonoids exhibit pleiotropic effects and can modulate inflammatory regulatory nodes (Fig. 7). The anti-inflammatory effect of flavonoids can be mediated in many ways; a) antioxidant effects, b) inhibition of inflammation-related gene expression, c) interactions with signaling pathways, d) interactions with inflammation-inducing proteins.

Anti-inflammatory mechanism of action
Flavonoids have anti-inflammatory activity through many actions including a) inhibition of transcription factors and regulatory enzymes that have a crucial role in the control of mediators involved in inflammation, b) additionally they are able to scavenge ROS and to enhance immune mechanisms and cells, c) modulation of secretory process, d) their effect on the arachidonic acid enzymes by inhibiting of lipoxygenase activity, e) modulation of signal transduction, f) inhibition of leukotriene synthesis, g) inhibition of cytokines production (Prostaglandins, No synthase, IL, TNF-alpha), h) modulation of enzymatic activity, i) inhibit COX-2 ( Fig. 7). (Table 4).

Structure activity relationship for anti-inflammatory
Typically, the structural activity of flavonoids as anti-inflammatory agents is examined as follows: a) -C = O groups at C-4 b) position and number of OH groups c) non-glycosylated d) methoxylated e) glycosides with high lipophilicity f) and ring unsaturation [91] (Fig. 8, Table 5).
The most important sites in flavonoids as anti-inflammatory are the C 2 and C 3 double bonds, 3 ', 4' OH in the B-ring and 5, 7 OH in ring A. The OH group is important for anti-inflammatory activity and for the inhibition of lipoxygenase activity [126]. Therefore, flavonols are more potent than flavones. The increase in the number of OH groups in ring B leads to increased anti-inflammatory activity. The introduction of the sugar fraction at the C 3 , C 7 or C 8 positions significantly reduce the anti-inflammatory activity, indicating the importance of structural lipophilicity and bioavailability [137]. In addition, the OH groups at C 4 ', C 5 or C 7 and their arrangement are responsible for the activity. The C 5 OH in A ring is important for activity because of its interaction with C 4 carbonyl group (-C = O), which forms intramolecular hydrogen bonds  and increases its activity, whereas substitution causes decreased activity. Likewise, the C 3 and C 7 OH groups are important for increasing activity, and their replacement decreases activity. The introduction of substituents at C 8 leads to a slight decrease in activity [138]. The presence of the OCH 3 group increases the inhibition of lipoxygenase activity because it increases the lipophilicity and bioavailability of flavonoids and changes the pharmacokinetic behavior [126]. . They reduce the levels of aspartate and alanine aminotransferase (AST and ALT, respectively) and pro-inflammatory cytokines in the serum and prevent the phosphorylation of NF-κB/p65, IKK, and IκBα in the NF-κB signaling pathway. Besides,flavonoids can inhibit hepatocyte apoptosis through suppressing caspase proteins and increasing Bcl-2 / Bax ratio [88]. Treatment with cyanidin-3-O-β-glucoside inhibits the release of inflammatory cytokines, reduces liver peroxidation, and prevents the development of hepatic steatosis (Zhu et al., 2012).

Hepatoprotective mechanism of action
Flavonoids have hepatoprotective activity through many actions like maintaining normal fluidity and stability of cell membrane, reversible inhibition of cytochrome P-450, ribosomal RNA synthesis, reduction of lipid peroxidation level, reduction of DNA damage, and decrease of protein carbonylation (ElGengaihi et al., 2016b) ( Fig. 9, Table 6).
It has been reported that silymarin increases the enzymatic activity of DNA-dependent RNA polymerase 1 and subsequently RNA, DNA and protein biosynthesis, that leads to cell proliferation, leading to regeneration of liver cells (Sonnenbichler et al., 1986). The therapeutic properties of silymarin include scavenging of ROS, collagen production, regulation of cell membrane integrity and permeability, inhibition of NF-κB activity, and inhibition of leukotrienes and kinase depression (He et al., 2004).

Structure activity relationship for hepatoprotective activity
The double bond at the C 2 and C 3 in ring A and the OH groups of C 3' or C 4' in ring B increases the protective activity, but the hydroxymethylation effect at C 3' and C 4' is reversed (Fig. 10). In addition, apigenin has good hepatoprotective activity and good potential as promising therapeutic anti-inflammatory agent [88].

Potential against hypertension
Mechanically, flavonoids mediate antihypertensive effects [230] by increasing the bioavailability of NO, modulating vascular ion channel activity and decreasing oxidative stress in endothelial cells. At the endothelial level, flavonoids exert a vasorelaxant effect mainly by elevating NO levels through various mechanisms such as increasing the bioavailability of NO, increasing eNOS activation via the PI3K / Akt / eNOS cascade and increasing Ca levels.

Antihypertensive mechanism of action
Mechanistically, antihypertensive effect of flavonoids is mediated by increasing NO bioavailability, modulation of vascular ion channel activity or reduction of oxidative stress in endothelial cells (Fig. 11, Table 7).

Structure activity relationship
In general, there are two speculations that could be responsible for the high vasorelaxant effect of flavonoids: a) those with a planar structure, the same flavonoid basic skeleton and the -C = O group attached to the C 4 position of the C ring, b) those with the same substituent attached to the C 5 position of A ring and the C 3' and C 4' positions of ring B (Fig. 12).

Potential against cardiovascular disease
Currently, flavonoids are attracting a lot of attention in the prevention of cardiovascular diseases (CVD). Foods rich in flavonoids have a positive effect on CVD. Evidence for the activity of metabolized and unmetabolized flavonoids in the three defense pathways in heart diseases is highlighted: NO bioavailability, induction of antioxidant enzymes, and anti-inflammatory processes. Table 4 List of flavonoids with anti-inflammatory effect and their mechanism of action.

Cardioprotective mechanism of action
Flavonoids have a positive effect on the cardiovascular system through various mechanisms. Although the direct mechanism is not understood, the effects of flavonoids appear to be diverse and dependent on many processes. The main pathways include anti-inflammatory and antioxidant activity, anti-platelet effect, anti-ischemic, anti-obesity, anti-atherolsclerosis, dyslipidemia, anti-hypertensive, anti-diabetic, prevent endothelial dysfunction, prevent heart hypertrophy, inhibit adhesion molecule production, regulating blood pressure, lowering cholesterol, and protecting LDL from oxidation (Fig. 13, Table 8). Flavonoids can reduce the inflammatory process via a variety of mechanisms, including NO inactivation, and inhibition of the entry of leukocytes into inflammatory sites [166]. In addition, flavonoids improve vascular function and modulate vascular endothelial inflammation [82]. Besides, flavonoids decrease the activity of enzymes that produce ROS, lipoxygenase, NADPH oxidase, and xanthine oxidase [165]. Flavonoids increase adenosine monophosphate kinase activity leading to inhibition of the rate-limiting enzyme for cholesterol synthesis [268]. Inhibition of COX and lipoxygenase by flavonoids leads to reduction in thromboxane and leukotriene synthesis and thereby leads to decrease in vasoconstriction [98]. Flavonoids showed decreased vascular cell adhesion molecules and C-reactive protein [163]. Flavonoids' inhibitory action of platelet aggregation is associated with the inhibition of the compounds that impair endothelial function and the formation of NO in the vascular endothelium [260].

Structure activity relationship for cardioprotective activity
The sequence of effectiveness of cardioprotective flavonoids is as follows descendingly; apigenin and luteolin, and kaempferol and quercetin followed by genistein and daidzein, then naringenin, then floretin and finally catechins then epicatechins. Analysis of the relationship between structural activities revealed that 5-OH, 7-OH, 4'-OH are essential for good cardioprotective activity. While, the presence of a glycosylated group significantly reduces cardioprotective activity. In addition, molecular volume and total energy predict the cardioprotective activity of flavonoids.

Potential against ulcers
Flavonoids are one of the most important types of phytocompounds Fig. 9. Flavonoid mechanism of hepatoprotective activity.

Table 6
List of flavonoids with hepatoprotective effect and their mechanism of action. used in ulcer therapy especially to combat Helicobacter pylori (H. pylori) [5]. Rutin was investigated for its anti-ulcer effect against gastric lesions due to its anti-lipoperoxidation effect in addition to its antioxidant potential, which reduces gastric MPO activity, increases nitrite / nitrate, exhibits NO production and increases GSH activity [83]. The various flavonoids of Oroxylum indicum have been used for centuries to treat various gastric ailments [249]. It was also found that several substituted flavones showed good gastroprotective activity. Flavonoid glycosides exhibit gastroprotective properties in mice exposed to multiple ulcer causes. It has been demonstrated that 5-methoxy-49-fluoroflavone is very effective as anti-ulcer agent [16].

Antiulcer mechanism of action
Flavonoids provide a cytoprotective effect by increasing levels of endogenous prostaglandins, increase mucus, reduce gastric PH, release myeloperoxidase reducing histamine secretion, inhibiting H. pylori, scavenging ROS and antisecretory mechanisms (Fig. 14, Table 9) [51,191]. The gastroprotective effect of resveratrol is sufficiently based on its potential to inhibit the production of important inflammatory mediators, to inhibit the expression of NF-κB and intracellular transcription enzymes (MAPKs) [110] and to decrease gastric MPO activity, decrease MDA, increase the collagen content and restore depleted GSH. Flavonoids play an important role in its therapeutic function in gastric tissue by inhibiting TNF-α. These polyphenols also reduce the elevated levels of lucigenin and luminol chemiluminescence, which indicate a

Structure activity relationship
The presence of a OCH3 group at the position C-7 appears to enhance gastroprotection. The presence of OH groups in C7 and C5 in flavones reduces their gastroprotective activity. The double bonds in the intact C-2 and C-3 and C-ring appear to be required for the strong activity [180]. Replacing the aromatic B ring with eitheralkyl group or heterocyclic ring or indole does not alter the gastroprotective properties [30].

Potential against diabetes
Flavonoids, which have strong antioxidant activity, are believed to be beneficial for treating diabetes [100]. The potential of antioxidants to protect against harmful effects of hyperglycemia, as well as to improve the metabolism and absorption of glucose, should be viewed as a major alternative in diabetes treatment [181]. In addition to their antioxidant effects, flavonoids can act on α-glycosidase which is considered as one of the biological targets involved in diabetes type 2. As free radical scavengers, flavonoids can effectively prevent and / or treat diabetes type 2.

Table 7
List of flavonoids with antihypertensive effect and their mechanism of action.

Antidiabetes mechanism of action
Flavonoids have a beneficial effect on diabetes through many pathways such as a) decrease cholesterol synthesis and TG levels, increase functional availability of antioxidants, increase insulin sensitivity glucose utilization, improve cell function and insulin action, reduce carbohydrate metabolism (Fig. 15), they interact with various signaling and metabolic pathways in pancreatic β cells, skeletal muscle, adipose tissue, and liver. Flavonoids increase glucose absorption by white adipose tissue and skeletal muscle. They affect β cell function, mass, insulin sensitivity, energy metabolism and stimulate protein kinases, which are essential for maximum glucose uptake stimulation [21].

Structure activity relationship for Anti-diabetes
A study Xu (2010) reported that the di-OH groups at the C 3' and C 4' positions were effectively conjugated to α-glucosidase.
The lack of C 2 -C 3 double bonds and ketone groups on C 4 in the C ring reduces the inhibitory activity of α-glucosidase and xanthine oxidase. In addition, the presence of a cathecholic system in B ring in the absence of the C 2 ,C 3 double bond and the ketone group at the C 4 position is not significant enough to demonstrate antidiabetic effects. In addition, the acetylation or alkylation of the OH groups in ring A decreases flavonoids bioactivity, demonstrating their inability to interact with enzyme binding sites and scavenging ROS. In summary, the results of the antidiabetic analysis indicate that the chemical criteria for the flavonoids bioactivity are very important (Fig. 16). The alkyl substitution is important determinant of antidiabetic activity when compared to spine alone. Both the configuration and the number of OH groups have a significant influence on the radical scavenging mechanism [253] and the antidiabetic effect. Therefore, the hydroxyl-configuration, number of OH groups, C 2 ,C 3 double bonds and functional C 4 ketone groups are the main structure features of flavonoid bioactivities, especially with regard to the antidiabetic effect.

Potential against fungal infections
Fungal infections cause high mortality rates worldwide. The incidence of increasing drug resistance in fungal diseases continues to increase. The scenario for the existing antifungal drugs and their complications is critical. Antifungal drugs have limitations: high toxicity, renal failure, and low performance. Therefore, it is important to seek new treatments, such as alternative therapies, that may be more active against most fungal diseases. Plants and herbs that contain flavonoids are known for their many therapeutic activities. Various flavonoids have been studied for their antifungal activity and are perhaps the promising, and most potent agents for inhibiting fungal infection [104,12,197,231]. They often inhibit fungal growth in various mechanisms of actions and increase plasma membrane damage and mitochondrial dysfunction, and inhibit cell wall formation, cell division, protein synthesis and the pumping system. These flavonoids are capable and effective in synergistic combination therapy with conventional drugs, which may be more suitable and supportive in finding new drug therapies to fight fungal pathogens ( [205]; Jin, Y.S., 2019).

Antifungal mechanism of action
Flavonoids have been widely used for centuries to inhibit fungal growth through various mechanisms (Fig. 17, Table 10). The way flavonoids work as antifungal agents is based on the induction of apoptosis, DNA fragmentation, mitochondrial damage, accumulation of ROS, etc.

Structure activity relationship for antifungal activity
The three main molecular properties that affect the antifungal activity (Fig. 18) are as follows:

Potential against cancer
Cancer is a terrible disease all over the world and one of the biggest problems for human health. New techniques are needed for successful treatment. Many limitations have been noted with conventional Table 9 List of flavonoids with gastroprotective effect and their mechanism of action.  treatments, including the high cost and high toxicity of current cancer drugs. Such a situation poses great challenges for all scientists and requires the development of new drugs that are environmentally friendly and have a more financially sound methodology. In this context, the high biodegradability and biocompatibility of phytocombinants increase their effectiveness in treating cancer [1]. In this sense, special attention is paid to improve cancer drugs using plant phytocompounds. Their potential, availability and low cost compared to modern therapeutic drugs for the treatment of dangerous diseases make them more attractive [184] (El Gengaihi et al., 2016a, 2016b).

Anticancer mechanism of action
So far, various mechanisms have highlighted the role of flavonoids in cancer therapy (Fig. 19, Table 11), including inhibition of proteasomes, induction of apoptosis, differentiation and cell cycle arrest [132,133,243], inhibition of nuclear factor signaling [13], and receptor interaction [96]. In addition, flavonoids may exhibit specific cytotoxicity for cancer cells, which is drawing much attention to flavonoid cytostatics as anticancer prodrugs [296].

Structure activity relationship for anticancer activity
The important role of the C 2 =C 3 double bond is essential for strong tumor inhibition [132,133,96]. In addition, greater inhibition will occur if the two hydroxyl groups of ring B exist side by side and C 2 =C 3 is unsaturated [96]. It should be noted that many reports provide evidence of the effect of hydroxylation on tumor modulation. Specific hydroxylated flavonoids have a stronger inhibitory effect on cancer cells than permethoxylation analogs. It is proposed to replace the B ring as a catechol part with vital influence. Meanwhile, the additional substitution of hydroxyl groups on ring B does not change the activity [132,133]. In the case of the C ring, 3-hydroxylation is seen as a very important component in enhancing the biological effect [13]. The flavonoid derivatives of O-methylation contribute to increased biological activity, which is often associated with ring A polymethoxylation. According to previous studies, glycosylation does not contribute to the induction of cell differentiation [132,133] (Fig. 20).

Potential against bacterial infection
The development of antibiotic resistance in bacteria is a global problem that requires the search for more potent phytocompounds derived from nature to overcome this problem. Flavonoids are phytocompositions with antibacterial, antioxidant and anti-inflammatory potential. In this way, flavonoids can be developed into new antimicrobial agents in food and therapeutical products.

Antibacterial mechanism of action
The proposed flavonoid antibacterial mechanisms (Fig. 21, Table 12) are mainly as follows: Inhibition of energy metabolism, inhibition of cell proliferation, inhibition of nucleic acid synthesis, reduction of biofilm formation and cell adhesion, attenuation of pathogenicity [54] and damage to membranes possibly by producing hydrogen peroxide ( Cushnie and Lamb, 2005).

Structure activity relationship for antibacterial activity
The amphipathic properties of flavonoids play an important role in their antibacterial properties [65]. Hydrophobic substituents like alkyl chains, alkylamino chains, prenyl groups and heterocyclic units containing oxygen or nitrogen usually increase flavonoids antibacterial activity [285]. The number and position of the prenyl groups in ring A increased activity, but the addition of the prenyl groups to another ring decreased activity. In addition, it has been reported that the presence of OH groups at different positions on rings A and B increases antibacterial activity [172,173,194,195]. The number of glycosyl groups instead of OH groups at position 3 also plays a crucial role in the antibacterial activity (Fig. 22). The only substitution that reduces activity is Table 10 List of flavonoids with antifungal effect and their mechanism of action. Apigenin Interfere with the translational activity of fungal foot-and-mouth disease [213] Carvacrol Inhibit nucleic acid synthesis Disrupt the cellular cytoplasmic membrane Induce apoptosis [305] Lico A [37]  methoxylation of position 3 [20].

Potential against viral infection
Viral infections are very difficult to control than bacterial infections, while antiviral agents are the least available. Natural phytocompounds provide a powerful resource for antiviral agents. Flavonoids exhibited potent antiviral activity (Table 13) [295]. Flavonoids stop HIV cell by the phosphorylation of proteins and inhibition of cytokines [147,150,19,201].

Flavonoids potentiality against CoVs
Coronavirus is responsible for the increasing severity of death causing COVID-19 disease. However, there is still a lack of antiviral drugs that are effective against the coronavirus. In short, there is a worldwide need for concerted efforts to combat such disease in the future. Most of the publications focus on polar compounds. Compounds that show promise in inhibiting coronavirus are scotelarein, silivestrol, tryptanthrin, saicozaponin B2, myricitin, quercetin, caffeic acid, isabavacalcone, and psoralidin. The most promising small molecule identified as a coronavirus inhibitor has been found to contain a conjugated fused ring structure, most of which are classified as flavonoids. An important area of research is the inhibitory effect of flavonoids on the coronavirus. Flavonoids existing naturally offer a large amount of biological diversity, including antiviral activity, and therefore may be useful as therapy against coronavirus infection. Flavonoids can prevent or modulate SARS-CoV-2 infection by many mechanisms (Fig. 23, Table 14) such as inhibiting spike glycoprotein, N protein, TMPRSS2 replication protein, ACE-2 entry receptor, protease, helicase, RNAdependent RNA polymerase, activating Nrf2, and stimulating innate immunity ( [295]; Antonio et al., 2020; Fuzimoto and Isidoro et al., 2020;[50,227,264,265,283]).

Structure activity relationship for antiviral activity
Structurally, the antiviral activity increases with the decrease in the number of OH groups in the B-ring. Meanwhile, the C 2 =C 3 double bond present in the C ring is seen as an important element which is beneficial for antiviral activity. In addition, trifloroside belongs to the group of dihydrocarbons without a flavonol structure, which has very little antiviral activity. This may be due to the hydrogen bonding formed by the galloyl group with amino acid residues at the active site of the enzyme [43].
Flavonoids exhibited significant binding at the N 3 -binding site compared to the main CoV protease inhibitor currently used, darunavir. The flavonol basic structure and the presence of a routine unit at position 3 in ring C and the absence of OCH 3 group on the B ring of the

Flavonoids as
An�cancer agent

Inhib�on of tumor cell invasion
Inhibi�on of protein kinase An�angiogenic proper�es Fig. 19. Flavonoid mechanism of anticancer activity.

Table 11
List of flavonoids with anticancer effect and their mechanism of action.  flavonol structure can increase the anti-COVID-19 activity [295]. Fig. 24 shows the interaction between phenyl group in kaempferol and corona virus catalytic center, which is the hydrophilic task of the corona virus through hydrogen bonding with Glu166. Another hydrogen bond is formed between the OH group and Asp142, Ile188, while the chromen-4-one backbone is at the hydrophobic S2 site [119].

Conclusion and future approaches
In order to summarize the ongoing review, some main points are to be highlighted. Flavonoids could be effective drugs against the most dangerous degenerative diseases in the future. Compared to other natural plant phytochemicals, flavonoids can significantly enrich the pathways of breast cancer, Huntington's disease, Alzheimer's disease, insulin resistance, and drug resistance. In this regard, its versatile therapeutic capabilities demonstrate the usefulness of flavonoids in producing drugs related to cancer and the nervous system.
Various physicochemical and structural properties of flavonoid can be attributed to differences in activity and can be found in physicochemical characteristics, including H bond donors, H bond acceptors, topological polarity surface area and water-lipid partition coefficients, because the proper solubility and water lipid partition coefficient play an important role in the effectiveness of the drug.
Since flavonoids contain the same skeleton, the functional differences are mainly related to the replacement groups. The relationship between the chemical constitution fragments and the biological effects  suggests that significantly different side chains can influence flavonoid activity in the same target. Apart from general biological functions, the specific functions of the various subclasses of flavonoids were analyzed and demonstrated at the target and pathway levels. For example, flavones and isoflavones were significantly amplified in a pathway associated with more cancers than others, suggesting potential therapeutic benefits in treating cancer. Flavan-3-oles have also been found in cellular processing and lymphocyte regulation, flavones have a specific effect on cardiovascular activity, and isoflavones are closely related to cellular multisystem disorders.
Cumulative structure activity relationship findings from previous pharmacological reports provide useful evidence for the role of different functional groups in nutritional benefits. Based on the description above, it can be concluded that the 4-carbonyl group, the C 2 =C 3 double bond, and the hydroxylation pattern, especially the 3-OH and catechol residue in the B ring, are the main known factors of the therapeutical effects of flavonoids. For example, the beneficial effect of hydroxylation is achieved in terms of exclusive antiviral, antibacterial, cardioprotective, anti-diabetic and carcinogenic effects. O-methylation is useful for antiviral, antibacterial, anti-diabetic, but of lower benefit for   anti-inflammatory and anti-cancer effects. In general, glycosylation can reduce the associated activity as anti-Alzheimer's disease, but on the contrary increases the antiviral and antibacterial effects. However, future approaches and further research efforts at the clinical level and in the field of bioavailability will provide a deeper understanding of the therapeutic effects of flavonoids on human health in general.

Conflict of interests
The author declares that they do not have any conflict of interests.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.