**3. Role and function of flavonoids as a protective preventive and curative effect against various diseases**

Therapeutic flavonoids are associated negatively with sickness, according to epidemiological research. Conventional flavonoids can interact with key enzyme systems and show polypharmacological action. It follows that the considerable study of chemical structure-activity connections is not surprising. Strong antiviral properties of bioactive flavonoids, including those against the hepatitis C virus, and antimicrobial such as *Escherichia coli*, have been examined. Chemical processes, including methoxylation, glycosylation, and hydroxylation, have been mostly responsible for these effects. Research on the structure-activity relationship (SAR) covers several elements. C2C3 double bonds are frequently advantageous—hydroxylation substitution style is important [46–49].

A beneficial role for 5�/7-hydroxyl derivatives in ring A hydroxylation is suggested by six anti-H5N1 influenzas A virus 5, 7-diOH flavonoid candidates, and daidzein's less potent anti-human fibroblast collagenase catalytic domain (MMP1ca) activities. Better ring B hydroxylation indicates stronger MMP1ca inhibition by 3<sup>0</sup> -OH and 5<sup>0</sup> -OH drugs. Catechol is the most common functional group. Innovative drug production has been stimulated by quercetin, more notable than morin inhibition of canine distemper virus [50, 51]. Compared to luteolin, quercetin considerably contributes to ring C. It also affects how many hydroxyl groups there are. More hydroxyl groups lessen the hydrophobicity of flavonoids, preventing membrane partitioning. Hydrophobicity and electronic delocalization impact the intensity of hydroxylation, which causes some hydroxyl-rich flavonoids to act more strongly. Different hydroxyl groups may raise C3 charges while decreasing hydrophobicity, which suggests pharmacological activity. Methylation hurts membrane fluidity and lowers the activity of several viruses and bacteria according to their physiology. Two PMFs performed less well against *E. coli* than equivalent aglycone. Antiviral activities can be found in flavonoid glycosides [52–54]. Finding the right screening substances for dietary

therapy and medical treatment may result from analyzing the SAR behaviors displayed by certain flavonoids in antiviral/bacterial situations. Apoptosis induction, proteasome inhibition, nuclear factor signaling suppression, differentiation induction, cell cycle arrest induction, receptor contact, and interaction with carcinogenic enzymes are a few of the mechanisms that have highlighted the importance of flavonoids in cancer therapy. Flavonoids have potential as anticancer medications since they can selectively kill cancer cells. The molecular planarity and conjugation between rings C and A/B that the C2C3 double bond produces are necessary to prevent tumor growth. Studies on the C2C3 double bond and its anticancer properties have been conducted using tumor cell lines, such as colon adenocarcinoma cells. Stronger inhibition was obtained by the C2C3 unsaturation and two hydroxyl groups on ring B [55, 56].

Numerous studies have demonstrated how hydroxylation affects tumor regulation. Per-methoxylated flavonoids do not have the same anticancer effects as hydroxylated flavonoids. To, 6-OH and 5, 7-diOH contribute, Ring B does not become less active when hydroxyl groups are added [1]. Ring C's 3-hydroxylation enhances its biological actions. Without 3-OH, flavonoids have less antiproliferative activity. The 3-OH molecule's affinity for the binding site might be greater [30, 57]. Methylated flavonoids support the enhanced biological action of ringing A polymethoxylation. Among the Organ flavonoids tested in the cell morphology research, two A-ring PMFs exhibit the highest proliferative inhibition, demonstrating the significance of the C-8 position in flavonoids' antiproliferative impact. The bioactivity of flavonoids against neurodegeneration has traditionally been linked to their antioxidant properties. However, new research has highlighted the significance of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) interactions, mitochondrial dysfunction, key neuronal signaling pathways, and chelation of transition metals in controlling neuronal resistance to neurotoxic oxidants and inflammatory mediators. Ring B hydroxylation may improve learning to avoid cardiovascular disease.

Effects of flavonoids and the eNOS transcription factor the second Krüppel-like component [58, 59]. The C2C3 double bond produces an effective twofold structure in eNOS and ET-1 synthesis, and 4-carbonyl moiety results in about 1.35-fold higher gene expression (quercetin vs. epicatechin/catechin), according to the findings. The "protein-binding" mechanism was highlighted in a SAR examination of 12 flavonoids with paraoxonase1 (rePON1) due, at least in part, to different hydroxylation substitutions, the C2C3 double bond, and the 4-carbonyl group in ring C. Flavones and flavonols have stronger PON1 interactions because of the C2C3 double bond in ring C, which increases molecular planarity and may cause electron delocalization between rings A and B. Coplanarity exists between the 3-hydroxyl group and the 4-carbonyl oxygen atom. Flavonoids' greatest therapeutic benefits are in managing leukemia, sepsis, asthma, and other inflammatory diseases. SAR research is more important because flavonoids have been extensively investigated and certain mechanisms may not be unified. Double bonds in C2C3 might encourage molecular planarity. For example, Hesperetin's absence results in a lower volume/surface ratio than diosmetin's absence [19, 50, 60]. (b) Isoflavones, the ring B catechol moiety, are subject to 3<sup>0</sup> - and 50 -hydroxylations that promote cell differentiation. (c) Ionizing hydroxyl groups and blocking the NF-kB signaling pathway during methylation boost the antiinflammatory impact. (d) Because of their decreased hydrophobicity and sterical hindrance, glycosides with lower lipophilicity have fewer anti-inflammatory effects [50, 61]. Moreover, a large replacement has been researched. Anti-inflammatory flavonoids have three taxonomic markers: the C-butyrolactone moiety, the 5-acetic

#### *Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning… DOI: http://dx.doi.org/10.5772/intechopen.108637*

acid/lactone group, and the C7C8 double bond. DM is a sophisticated hyperglycemic condition. The flavonoids that fight diabetes are widely recognized. By hydroxylation and planarity at position 7, several flavonoids can activate PPAR. Methoxylation enhances the antidiabetic efficacy of flavonoids on 3 T3-L1 adipogenesis, but hydroxylation has a detrimental effect [62–64]. SAR is the substitution of glycosylation, particularly glucosylation at position 3. C-3-Glu/detail. More proof is required on Gly's mechanism of glucose regulation. Transition metals that promote radical hydroxyl formation in reduced forms through the Fenton reaction can be bound by flavonoids. Due to the resorcinol moiety of ring A, isoflavone has the highest antioxidant activity among studied flavonoids. These numbers indicate the structural elements of antioxidants. SAR is aided by the C2C3 double bond conjugated to a 4-carbonyl group in the flavonoid subclasses ring C. According to some authors, there is no clear connection between these moieties and antioxidant function when other structural conditions are satisfied. Despite cellular ROS inhibition and structural moieties being similar, certain flavonols have strong electron-donating action [32, 65, 66]. A C2C3 double bond conjugated to a 4-carbonyl group improves antioxidant activity when other structural requirements are satisfied. The dissociation constant of phenolic hydroxyl groups and the stability of phenoxy radicals in ring B are both impacted by the 4-carbonyl group's propensity to create electron shifts through resonance effects. Ring C and A/B can be conjugated thanks to the electron coupling and molecular planarity provided by the unsaturated C2C3 double bond. Likewise, 5-OH creates hydrogen bonds. 4-Carbonyl delocalizes the ring B electron, increasing the antioxidant effect when combined with the C2C3 double bond or other electron-donating groups. The degree and location of hydroxylation affect how anti-oxidative flavonoids are. Stable flavonoid radicals are created when hydroxyl groups on the ring B absorb hydrogen and electrons. Two hydroxyl groups in ring B considerably increase antioxidant activity [67–70]. The primarily responsible pharmacophore is the 3<sup>0</sup> , 4<sup>0</sup> -catechol group, which generates an ortho-semiquinone radical by electron delocalization and confers high activity through intra-molecular hydrogen bonding between catechol hydroxyl groups. Outside of the two hydroxyl groups on ring B, no one substitution makes sense. With 4<sup>0</sup> - OH, apigenin promotes erythroid differentiation. Higher inhibitory effects were seen from flavonoids with an ortho-dihydroxyl group in ring B than those with a 4<sup>0</sup> hydroxylation. In comparison to ring A's meta-dihydroxylation, ring B's orthodihydroxyl group is more easily oxidized 5, 7-di-OH in ring A inhibits the activity of antioxidants. Strong 5- and 7-OH as 2, 4-substituted resorcinol substructure activities are highlighted by luteolin, quercetin, kaempferol, and apigenin [71–73]. There is proof that alterations in ring A's positions 5 and 7 that donate electrons prevent the 3-hydroxylation of ring C. 3-OH inhibits antioxidant activity compared to luteolin and quercetin. When examining overall hydroxylation, both the electron transit within the resonance system and the total hydroxyl groups are considered. The flavonoid nucleus with more hydroxyl groups is held up in the hydrophobic cavity because hydrophilicity rises with the number of hydroxyl groups [18, 74, 75]. The antioxidant activity is decreased by altering the methylation of the free hydroxyl groups on ring B. Methoxyl flavonoid derivatives have higher antioxidant activity due to flavonoid-flavonoid interaction [76, 77]. Ring A's several methoxylation substitutions should offset the catechol moiety of ring B. Antioxidant activity of flavonoid O- or C-glycosides has been investigated. Chemical tests have shown that c-glycosides are more effective antioxidants than O-glycosides. Compared to O-glycosides, C-glycosyl flavonoids exhibit about 100% higher radical scavenging action [53, 73, 78]. Another experiment shows that the antioxidant activity of c-glycosides is roughly 50%. The

aforementioned C-glycoside studies still require in vivo information and in-depth analysis. Flavonoid glycosides develop in food as A- or C-ringed O-glycosides. The author speculates that the sugar moiety in position 3 could exacerbate steric hindrance or polarity. In addition, ring A's antioxidant capabilities are enhanced by 6 glucosylation but diminished by 8-glucosylation [54, 79].
