*2.1.3.2 The biological activity of tropane alkaloids*

#### *2.1.3.2.1 Effect on asthma*

Atropine is extracted from the dried leaves and blooming tops of Datura metal, a member of the Solanaceae family. It works against Nocturnal Asthma. Atropine methyl nitrate can successfully cure nocturnal asthma, atropine sulfate [66], atropine in combination with metaproterenol [67], and albuterol Correspondingly. Atropine inhalation can enhance lung mucociliary function in humans.

#### *2.1.3.2.2 Activity against hyperglycemia and parkinsonism*

Atropine reduces hyperglycemia caused by neostigmine [68]. Atropine affects diabetes individuals' vagal tone [69]. Atropine can relieve tremors in a monkey model of parkinsonism.

#### *2.1.3.2.3 Anti-cancer and anti-inflammatory activity*

Colchicine is beneficial against chronic myelocytic leukemia and gout at toxic or almost toxic doses [70].

#### *2.1.3.3 The biological activity of isoquinoline alkaloids*

#### *2.1.3.3.1 Anti-bacterial activity*

Berberine has antibacterial action at a minimum inhibitory concentration (MIC) of 78 μg/mL by severely disrupting bacterial cell membrane structure by inhibiting cellular proteins, as proven by TEM and SDS-PAGE. This substance influenced bacterial DNA synthesis. It also inhibits methicillin-resistant S. aureus (MRSA) biofilm development in a concentration-dependent manner ranging from 1 to 64 μg/mL by reducing phenol soluble modules (PSMs) aggregation into amyloid fibrils.

#### *2.1.3.3.2 Anti-diabetic activity*

Berberine (methanolic extract) has anti-diabetic activity at a dosage of 500 mg/ kg. Berberis aristata (methanolic extract) has potential effects on glucose metabolism, as well as HDL and cholesterol levels, in addition to anti-diabetic action [71].

#### *2.1.3.3.3 Anti-osteoporosis activity*

Berberine has modest laxative and hypocholesterolemic properties [72]. Berberine and its methanolic extract have strong antiosteoporosis action, which supports its ethnic usage in the treatment of postmenopausal osteoporosis [73].

#### *2.1.4 Current and potential industrial applications of alkaloids*

#### *2.1.4.1 Pharmaceutical application*

Alkaloids have led to the development of herbal remedies and their components based on the medical approach. The alkaloidal structure is changing chemically to improve therapeutic response. In general, synthetic medications perform better after modification than natural pharmaceuticals. Alkaloids, on the other hand, play an important part in phototherapy, homeopathy, and alternative medicine [15]. Indole, isoquinoline and tropane compounds are clinically important. In the pharmaceutical business, natural medications are transformed into medical goods to get a greater therapeutic response than synthetic pharmaceuticals. Physicians are interested in prescribing herbal treatments for the treatment of various ailments. Tropane derivatives such as atropine, hyoscine, and hyoscyamine are widely advocated for both recreational and therapeutic uses. Atropinol, for example, comprises the active component of atropine sulfate. Buscopan is a hyoscine derivative. Transdermal plasters include it. Another component of Bella sanol is hyoscyamine [15, 74]. Key alkaloids including boldine, codeine, narceine, and morphine have important roles in clinical care. Oxyboldine and Bold oval have morphine-like pharmacological effects. Codeine is a common ingredient in over 250 medicinal medications on the market. Codicaps and Codipront can be used for the same thing. Every single product is derived from opium. Narceine-containing drugs are related to codeine. It is mainly used for cough treatment [15, 75]. Tubocurarine derivatives such as tubarine and jexin have been used to relax muscles. Morphine-containing medicines, such as morphalgin and spasmofen, are utilized in extreme circumstances like surgical procedures and postoperative care [15]. The indole alkaloid chemical constituents such as ephedrine, ergotamine, ergometrine, and yohimbine are used in various combination formulations. Ephedrine is the primary active component of Dorex or Endrine. It is used for a variety of applications, including the treatment of nasal cold symptoms and bronchial asthma [15]. Ergotamine is the primary chemical ingredient of ergot. Because of its several uses; ergotamine is widely accessible on the market. Ergostat and Migral are commercialized ergotamine-based medications. These alkaloids are used in the treatment of migraines. Yohimbine is the primary active molecule in aphrodyne or yohimex. Based on this alkaloid, at least 20 distinct compounds have been created. These medications are used to treat male impotency. Alkaloids have a wide range of applications. Strychnine, for example, is used to treat a variety of illnesses, including eye ailments. Strychnine, which is used in clinical quantities, is the active component of Dysurgal or Pasuma [15, 76].

#### *2.1.4.2 Agricultural application*

Alkaloids are a source of worry and debate in food crops due to potential health risks and the fact that they must be eliminated from plants through breeding, particularly hybridization. As a result, alkaloid-rich (bitter) and alkaloid-poor (sweet) cultivars are created [77]. Total alkaloids cannot be eliminated by breeding. However, by employing an appropriate application, alkaloid content can be reduced. Industrial processing also removes alkaloids from raw materials [15]. Alkaloids are sometimes used as biological fertilizers in agriculture.

Alkaloids are high in nitrogen and carbon. Nitrogen and carbon, on the other hand, play an essential role in organic farming. The balance of macro and micronutrients is critical in carbon and nitrogen-based soil management methods.

#### **2.2 Flavonoids**

Flavonoids are secondary metabolites that are abundant in plants, fruits, and seeds and are responsible for color, aroma, and flavor. Flavonoids have several roles in plants, including controlling cell development, attracting pollinators and insects, and defending against biotic and abiotic stressors [78]. These chemicals have been linked to a wide range of health advantages in humans, including anti-inflammatory, anticancer, anti-aging, cardioprotective, neuroprotective, immunomodulatory, antidiabetic, antibacterial, antiparasitic, and antiviral effects [79–81]. Flavonoids have a C6−C3−C6 flavone skeleton with two benzene rings (A and B) connected by a three-carbon pyran ring (C). The location of the catechol B-ring on the pyran C-ring, as well as the quantity and position of hydroxy groups on the catechol group of the B-ring, affect the antioxidant activity of flavonoids [82]. Flavonoids' functional hydroxy groups can donate electrons through resonance to stabilize free radicals and mediate antioxidant protection [83]. Flavonoids are categorized into six primary types based on their structure: Flavan-3-ols, Flavones, Flavonols, Flavanones, Isoflavones, and Anthocyanins [83]. Because of their remarkable antioxidant qualities, Flavonoids are used in the food, cosmetic, and pharmaceutical industries [84].

#### *2.2.1 Flavonoids biosynthesis, structure, and classification*

Flavonoids are phenolic chemicals or polyphenols that have over 6000 distinct configurations [83]. Flavonoids are generated from two biochemical processes in plants: the phenylpropanoid system, which generates the phenylpropanoid skeleton (C6−C3), and the polyketide pathway, which generates blocks for polymeric C2 units [85]. Almost all flavonoids have a C6−C3−C6 structure with two benzene rings, A and B, linked by an oxygen-containing heterocycle pyrene ring (C). Flavonoids are classified into two broad groups based on the degree of central heterocyclic ring saturation [79]. Anthocyanidins, Flavones, Flavonols, and Isoflavones, for example, have a C2〓C3 unsaturation, whereas Flavanones, Dihydroflavonols, and Flavan-3-ols are saturated flavonoids (**Figure 2**).

#### *2.2.1.1 Anthocyanins*

Anthocyanins are responsible for the hues of flowers, which range from pink to blue, but they are also found in leaves, fruits, and roots. Anthocyanins are the anthocyanidins O-glycosides from a chemical standpoint, as previously stated. Anthocyanidins (**Figure 2g**), which are highly oxidized 2-aryl-3-hydroxychromenylium, are also colored pigments, but they are less stable, so there are fewer examples in nature. The most common derivatives are cyanidin, which is responsible for red to magenta colors, delphinidin, which is responsible for purple to blue colors and pelargonidin, which is responsible for orange to pink colors (**Figure 3**). The presence

#### **Figure 2.**

*Types of Flavonoids (a) Chalcone, (b) Isoflavone, (c) Flavone, (d) Flavanone, (e) Dihydroflavonol, (f) Flavonols and (g) Anthocyanins.*

of a sugar moiety causes several color brightness alterations. The most frequent sugar with a β-linkage is glucose, but galactose, rhamnose, and xylose are also present [86].

#### *2.2.1.2 Flavanones and dihydroflavonols*

Flavanones, 2-arylchroman-4-ones (**Figure 2d**), are formed via ring closure isomerization of 20-hydroxychalcones, which results in a stereogenic center at carbon C2. As a result, naturally occurring flavanones are optically active, mostly with a (2S) stereogenic structure, as in naringenin (**Figure 4**), a structure seen in natural flavanones. Many natural flavanones are also connected to sugars, mainly *Secondary Metabolites: Alkaloids and Flavonoids in Medicinal Plants DOI: http://dx.doi.org/10.5772/intechopen.108030*

#### **Figure 3.**

*Examples of representative anthocyanidins and anthocyanins. (A) Cyanidin, (B) Delphinidin, (C) Pelargonidin, (D) Seranin, (E) Hyacinthin.*

as 7-O-glycosides, although others include prenyl side chains [87]. Dihydroflavonol, 2-aryl-3-hydroxychroman-4-one (**Figure 2e**), the biosynthesis of flavanones requires an oxidative hydroxy group addition at the C-3 position, which is why they are sometimes referred to as 3-hydroxyflavanones. Taxifolin is a common derivative that also serves as the principal scaffold for various other naturally occurring dihydroflavonols (**Figure 4**). These flavonoids are also discovered connected to sugars, with astilbin being an important example, as it has outstanding anti-inflammatory action [88] and is related to other groups such as prenyl and methoxy groups.

#### *2.2.1.3 Isoflavones*

Isoflavones, also known as 3-aryl-4H-chromen-4-ones (**Figure 2b**), are synthesized from flavanones by a rearrangement that favors 2,3-aryl migration followed by dehydrogenation. Although the word isoflavonoids is derived from the isolation of other

#### **Figure 4.**

*Examples of representative Flavanones and Dihydroflavonols. (a) (2S)-Naringenin, (b) Amorisin, (c) (2R,3R)- Taxifolin and (d) Astilbin.*

#### **Figure 5.**

*Examples of representative isoflavones. (A) Daidzein (B) Genistein.*

chemicals, such as isoflavanones or isoflavans, isoflavones remain the most prevalent. Isoflavones are still found only in a few subfamilies of the Leguminosae family [89]. Nonetheless, these metabolites have significant estrogenic action [90], and the antiinflammatory benefits of several therapeutic plants are due to their isoflavone content [91]. The most prevalent scaffolds are daidzein and genistein (**Figure 5**), which are also discovered coupled to sugars however, there are just a few cases.

#### *2.2.1.4 Flavones and flavonols*

Flavones, 2-aryl-4H-chromen-4-ones (**Figure 2c**), and flavonols, 2-aryl-3-hydroxy-4H-chromen-4-ones (**Figure 2f**), are formed via dehydrogenation of flavanones and dihydroflavonols, respectively. Flavones are the most common and typical class of flavonoids, moreover if it is considered that flavonols are 3-hydroxyflavones. Flavones have piqued the curiosity of scientists due to their abundance in nature and documented biological activity [92]. Flavones are further classified based on their substitution pattern and wide dispersion, such as O-methylated, C-methylated, and isoprenylated, among others. Flavones are members of the flavonoid family that exist as both O- and C-glycosides, with the most common aglycones being apigenin and luteolin (**Figure 6**). Although various sugar moieties have been identified, glucose is the most prevalent, and the flavone-preferred O-glycosylation site is C7. It's worth noting that many sugar units can be connected to C-glycosides, as shown in carlinoside (**Figure 6d**), the most common flavonol is quercetin (**Figure 6e**), which has

*Secondary Metabolites: Alkaloids and Flavonoids in Medicinal Plants DOI: http://dx.doi.org/10.5772/intechopen.108030*

#### **Figure 6.**

*Examples of representative flavones and flavonols. (a) Apigenin, (b) Luteolin, (c) Apiin, (d) Carlinoside, (e) Quercetin and (f) Rutin.*

numerous biological features established [93], and which exists in both aglycone and oglycoside forms. In the case of rutin, O-glycosylation occurs at C3 (**Figure 6f**). The most common flavonol glycoside in the plant kingdom.

#### *2.2.2 Sources of flavonoids*

Flavonoids may be found in a variety of drinks and foods, including wine, beer, and tea, but the largest concentrations of natural flavonoids can be found in fruits, vegetables, flowers, and seeds [94]. The quantity of these chemicals, however, is determined by various factors, including plant cultivar/genotype, growing environment circumstances, soil characteristics, harvest, and storage. Green leaves, fruits, and grains are high in flavonols such as quercetin, kaempferol, fisetin, isorhamnetin, and myricetin (**Table 3**) [95, 96]. Lettuce, cranberry, apple, peaches, and red pepper, for example, are high in quercetin and kaempferol [97]. Rutin, spinacetin glycosides, and patuletin glycosides are abundant in spinach leaves but kaempferol 3-O-glycosides are abundant in broccoli, kale, endive, potatoes, onions, grapes, and tomatoes [98]. Myricetin can be found in a variety of foods, including nuts, berries, tea, and red wine [98, 99]. Flavones, which include luteolin, apigenin, sinensetin, isosinensetin, nobiletin, tangeretin, galangin, and chrysin, are among the most significant flavonoids (**Table 3**) [95].


#### **Table 3.**

*Flavonoid classes and examples of natural food sources*

These chemicals are mostly found in leaves, flowers, and fruits as apigenin, luteolin, and diosmetin glucosides [96]. Apigenin-7-O-glycoside, for example, is plentiful in celery, while luteolin and apigenin glycosides are abundant in numerous citrus fruits, green and red peppers, lettuce, broccoli, olive oil, cocoa, oregano, thyme, rosemary, peppermint, and parsley [98]. Flavanols, also known as flavan-3-ols, are a group of compounds that include catechin, epicatechin, epicatechin gallate, gallocatechin, epigallocatechin, and epigallocatechin gallate (**Table 3**) [100]. Flavanols such as (−)-epigallocatechin gallate, (−)-epicatechin gallate, (−)-epigallocatechin, and (−)-epicatechin are abundant in Camellia sinensis, the tea plant, and tea drinking is one of the most significant sources of these flavonoids [101]. Furthermore, fruits high in (+)-catechin, (−)-epicatechin, and (−)-epigallocatechin include apples, red grapes, peaches, mangoes, pears, plums, nectarines, and raspberries. Catechins can be found in cocoa and red wine [97, 98]. Flavanones, also known as dihydroflavones, is a kind of flavonoid found in citrus fruits (**Table 3**). Flavanone glycosides such as naringin, naringenin, and naringenin 7-O-neohesperidoside may be found in grapefruits, hesperidin, hesperetin, and hesperetin 7-O-rutinoside in oranges, mandarins, limes and lemons, and eriocitrin, eriodictyol, and eriodictyol 7-O-rutinoside in lemons [96, 97]. Isoflavones have a more restricted distribution in plants, being generated mostly in legumes [102]. Soybeans are high in genistin, glycitin, and daidzin glycosides, as well as malonylated isoflavones [98] (**Table 3**). Genistin can also be found in lupin, fava beans, and kudzu roots. Isoflavones are found in small amounts in common beans, peanuts, and chickpeas [102]. Anthocyanins are flavonoids that give some flowers, foliage, and fruits their blue, purple, red, and orange colors. This family of chemicals is found in anthocyanidin glycosides such as cyanidin, pelargonidin, delphinidin, peonidin, petunidin, and malvidin [97]

#### *Secondary Metabolites: Alkaloids and Flavonoids in Medicinal Plants DOI: http://dx.doi.org/10.5772/intechopen.108030*

(**Table 3**). Cranberries, blueberries, raspberries, bilberries, strawberries, blackberries, plums, grapes, cherries, and sweet potatoes for example contain significant levels of anthocyanins [98]. Red cabbage, red turnips, and purple sweet potatoes are high in acylated anthocyanins. Furthermore, black beans, and purple maize contain cyanidin 3-O-glucoside [96]. Some flowers are blue because of delphinidin, while others are orange because of pelargonidin. Natural flavonoids can be isolated and utilized in the food business instead of manufactured chemicals to improve food quality.

In recent years, restrictions on the use of some synthetic antioxidants, such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and propyl gallate, have increased interest in natural flavonoids, owing to their ability to slow oxidative degradation of lipids, improve food quality and nutritional value and reduce toxicity [103]. Flavonoids can be utilized as food preservatives, preventing lipid oxidation and safeguarding vitamins and enzymes, as microbial growth inhibitors in foods, as additions in human nutritional supplements and animal feed, as flavorings, and colorants and as flavorings and colorants (e.g., anthocyanins) [103]. Some flavonoids also decrease fungal spore germination and have been recommended as a fungal disease control agent in certain meals [104]. Flavonoids are extremely adaptable, with photochemical capabilities that can be employed to protect drinks against light-induced color loss [105]. Because flavonoids are natural chemicals with low toxicity, plentiful in plants, and affordable, their rising usage as food additives in place of synthetic preservatives will contribute to the sustainability of the food business.

#### *2.2.3 Biological activity of flavonoids*

Flavonoids have been demonstrated to have various health advantages in humans and a diet high in these substances can help avoid several chronic illnesses [94]. Flavonoids have numerous functions, but the capacity to scavenge free radicals and serve as antioxidants is unquestionably the most important. The antioxidant potential of flavonoids varies depending on the kind of functional group and its placement around the nuclear structure [106]. The amount and location of hydroxy groups in the catechol B-ring, as well as their position on the pyran C-ring, affect free radical scavenging capabilities [82]. Flavonoids' antioxidant activity methods include (a) direct scavenging of ROS, (b) suppression of ROS creation via trace element chelation (e.g., quercetin possesses iron-chelating and iron-stabilizing capabilities), or inhibition of enzymes involved in free radical production (e.g., glutathione S-transferase, microsomal monooxygenase, mitochondrial succinoxidase, NADH oxidase, and xanthine oxidase) and (c) antioxidant defense activation (e.g., upregulation of antioxidant enzymes with radical scavenging ability) [97, 106]. The majority of flavonoids occur as glycosides and the number and position of linkages with the sugar determine the flavonoid's antioxidant effects [107]. However, aglycone forms have a stronger antioxidant capability but are less available. In addition to antioxidant capabilities, flavonoids have been shown to have anti-inflammatory, anticancer, cardioprotective, antibacterial, and antiviral activities (**Table 4**). Inflammation develops as a result of a variety of factors, including tissue physical damage or trauma, chemical exposure, and microbial infection. In most circumstances, inflammation is brief and self-limiting, but in rare cases, continuous inflammation contributes to the development of chronic or degenerative illnesses such as cancer, diabetes, cardiovascular and neurological diseases, and obesity [108]. Flavonoids can serve as antioxidants in an inflammatory process, (a) scavenging ROS or lowering free radical buildup, (b) inhibitors of regulatory enzyme activity (e.g., protein kinases and phosphodiesterase), and


#### **Table 4.**

*Flavonoid classes and some examples of their biological activities.*

transcription factors involved in the regulation of mediators involved in the inflammatory process, and (c) immune cell activity modulators (e.g., suppression of cell activation, maturation, signaling transduction, and secretion processes) [108]. The inflammatory process is influenced by both hereditary and environmental factors.

Several studies have shown that a nutritious diet rich in fruits and vegetables, as well as non-processed and low-sugar meals, along with an active lifestyle, might help avoid inflammatory disorders [108]. Some flavonoids, such as flavonols (e.g., quercetin, rutin, and morin), flavanones (e.g., hesperetin and hesperidin), flavanols (e.g., catechin), isoflavones (e.g., genisten), and anthocyanins (e.g., cyanidin) have been demonstrated to exhibit anti-inflammatory functions during in vitro and in vivo experiments and clinical studies.

#### *2.2.3.1 Cardiovascular protection*

Flavonoids can protect the heart by reducing oxidative stress (preventing the oxidation of low-density lipoproteins), causing vasodilation, and regulating apoptotic processes in the endothelium [109]. Flavonoids can interact with lipid metabolism and minimize platelet aggregation, hence avoiding a variety of cardiovascular disorders [110]. Some research has shown that quercetin, naringenin, and hesperetin have vasodilator characteristics, with naringenin lowering blood pressure and relaxing vascular smooth muscles [108]. Isoflavones appear to protect against inflammatory vascular disorders and quercetin possesses cardioprotective characteristics against heart damage as well as an atheroprotective activity linked to oxidative stress reduction [108]. Baicalin has been shown to prevent apoptosis in heart tissue and alleviate cardiac dysfunction [111]. Chrysin inhibits platelet activity, while genistein has antihypertensive characteristics [109]. Anthocyanins reduce the risk of myocardial infarction in humans, enhance systolic blood pressure, and lower triglyceride total, and LDL cholesterol levels [112]. Furthermore, quercetin lowers systolic blood pressure and LDL cholesterol levels [81].

#### *2.2.3.2 Antiviral action*

Flavonoids can inhibit virus binding and penetration into cells, interfere with viral reproduction or translation and impede virus release [113]. Apigenin, for example, has been shown to inhibit viral protein synthesis in various DNA and RNA viruses, including herpes simplex virus, types 1 and 2, hepatitis C and B viruses, and the African swine fever virus [114]. Baicalein can inhibit avian influenza H5N1 virus multiplication in humans [115], while luteolin can inhibit HIV-1 reactivation [115]. Epigallocatechin gallate has an antiviral impact at several stages of the HIV-1 life cycle [115]. By interfering with HIV-mediated actin dynamics, genistein can prevent HIV infection of CD4 T cells and macrophages [116]. In addition, kaempferol can limit HIV replication in target cells [117] and prevent herpes simplex virus types 1 and 2 from adhering to and entering the host cell [116]. Wu et al. demonstrated the antiviral activity of quercetin, kaempferol, and epigallocatechin gallate against different influenza virus strains [118].
