Plant Secondary Metabolites: Therapeutic Potential and Pharmacological Properties

Abstract

Plants are an essential source for discovering novel medical compounds for drug development, and secondary metabolites are sources of medicines from plants. Secondary metabolites include alkaloids, flavonoids, terpenoids, tannins, coumarins, quinones, carotenoids, and steroids. Each year, several new secondary metabolites are extracted from plants, providing a source of possibilities to investigate against malignant illnesses, despite certain natural chemicals having distinct anticancer activities according to their physicochemical features. Secondary metabolites found in plants are frequently great leads for therapeutic development. However, changes in the molecular structure of these compounds are improving their anticancer activity and selectivity and their absorption, distribution, metabolism, and excretion capacities while minimizing their toxicity and side effects. In this section, we will discuss the most significant breakthroughs in the field of plant secondary metabolites, some of which are currently in clinical use and others that are in clinical trials as anticancer drugs. This study gives an up-to-date and thorough summary of secondary plant metabolites and their antioxidant, antibacterial, and anticancer effects. Furthermore, antioxidant and antibacterial, and anticancer effects of secondary metabolites are addressed. As a result, this article will serve as a thorough, quick reference for people interested in secondary metabolite antioxidants, anticancer, and antibacterial properties.

1. Introduction

Plants are essential in pharmacological research and drug development, not only when bioactive substances are used as therapeutic agents directly, but also as starting materials for drug production or as models for pharmacologically active molecules. Secondary metabolites differ depending on the plant species. Secondary metabolites are molecules produced by plants that remain unknown in their roles in growth, photosynthesis, reproduction, and other primary processes. Secondary compounds are widely employed in plants, primarily in Asia [1]. Secondary metabolites boost human immunity because pharmaceuticals are mainly based on plant components. Secondary compounds in plants can serve as medicinal for humans [2]. Several criteria have been considered to classify secondary metabolites, including chemical structure, composition, solubility, and biosynthetic pathway [3].

1.1 Phenolics

Plants’ most critical secondary metabolites and bioactive chemicals are flavonoids and phenolic acids [4]. They’re also a natural antioxidant capable of scavenging free superoxide radicals, slowing the aging process, and lowering cancer risk. Flavonoids have been shown to reduce blood glucose levels in people. Phenolic acids Flavonoids have been found in several investigations [5]. Phenolic acid is a well-known class of secondary metabolites with a wide range of pharmacological effects. Phenolics are reported for various biological functions. Some of the effects of phenolics include enhancing bile secretion, lowering blood cholesterol and lipid levels, and antibacterial activity against bacteria such as staphylococcus aureus [6]. Antiulcer, anti-inflammatory, antioxidant, cytotoxic and antitumor, antispasmodic, and antidepressant properties are all found in phenolics and flavonoids [1, 4, 7]. Multiple glycoprotein VI signaling pathway components prevented collagen-stimulated platelet activation by dietary polyphenolic substances, particularly quercetin [8].

1.2 Phenolic acids

The phrase “phenolic acids” refers to phenolic compounds that have only one carboxylic acid group [9]. They are found in a different plant-based diet, with the most significant amounts in seeds, fruit skins, and vegetable leaves [10]. Plant phenolic acids are an essential part of the human diet because of their high antioxidant capacity and other health advantages. According to epidemiological studies, a diet with high antioxidant vegetables and fruits lowers the incidence of several oxidative disorders like cancer, diabetes, and cardiovascular disease. They also induced protective enzymes that positively affect signaling pathways, indicating indirect antioxidant activity [11]. Phenolic acids influence the action of glucose and insulin receptors. They increase the GLUT2 glucose transporter levels in insulin-producing pancreatic cells and stimulate GLUT4 transportation via the PI3K/Akt and AMP-derived kinase pathways. Ferulic and chlorogenic acids, for example, demonstrated the precise transporter activation mechanism and acted as anti-diabetic drugs [9, 12, 13, 14]. Among all the phenolic chemicals found in feces water, phenolic acids are the most prevalent [15]. They have antibacterial properties and can also be used as food preservatives. Phenolic acids and their derivatives play an essential role in cancer prevention and treatment [4, 9, 15]. Plant phenolics may be able to help in this area. Natural products or derivatives accounted for more than half of anticancer prescription medications approved globally between the 1940s and 2006, and numerous clinical trials are still ongoing [16]. They halt the creation of DNA adducts, thwart the synthesis of genotoxic compounds, and inhibit the mutagen’s activity [9, 17]. Most phenolics work at different locations to treat or inhibit various cancers [18].

1.3 Flavonoids

Flavonoids are a type of polyphenolic chemical that occurs naturally. It’s one of the most prevalent combinations found in vegetables, fruits, and beverages made from plants. Flavonoids are dietary supplements that promote health and prevent disease. It is now measured as an essential part of a wide range of nutraceutical, pharmacological, medical, and other products [19]. Aside from their antioxidant properties, flavonoids have a wide range of biological activities that contribute to human health [20]. Anti-inflammatory, antiulcer, antiviral, anticancer, antidiabetic, and cytotoxic actions are only a few examples. Flavonoids have shown various dietary benefits on antioxidant activity in multiple studies. Flavonoids also protect cell membranes from lipid peroxidation-induced damage. As a result, flavonoids play an essential role as antioxidants in oxidative stress-related illnesses [21]. Inflammatory disorders such as leukemia, asthma, sepsis, atherosclerosis, sclerosis, allergic rhinitis, psoriasis, rheumatoid arthritis, ileitis/colitis, and others have been linked to flavonoids. To eradicate foreign pathogens and restore wounded tissues, recruitment of inflammatory cells and release of RNS, ROS, and proinflammatory cytokines. Inflammation is usually quick and self-limiting, but abnormal resolution and protracted inflammation can lead to various chronic diseases [22].

Flavonoids similarly inhibit phosphodiesterases involved in cell activation. According to a different study, flavonoid-rich extracts from plants have antibacterial properties [22]. According to numerous studies, natural flavonoids have been exceptional antiviral action since the 1940s. They aid in the blockage of several enzymes involved in the virus’s life cycle. According to many studies, flavonoids such as hesperetin, quercetin, and naringin have anti-dengue action [23]. Flavonoids have a prominent effect on the immunological implications that occur through the genesis and progression of cancer. They can affect various biological signals in cancer, including vascularization, apoptosis, cell proliferation, and cell differentiation. Flavonoids mainly increase carcinogenicity’s start and promotion stages and influence expansion and hormonal activity [19, 20].

1.4 Terpenes

Terpenes are a diverse group of secondary metabolites in plants, with over 40,000 distinct compounds [24]. Terpenes are categorized based on how many isoprene units they contain. Terpenes are combinations of volatile molecules with characteristic odors found in the flowers and fruits of many plants, including mint, lemon, ginger, eucalyptus, and great basil [25]. They have a variety of biological roles and are involved in plant’s metabolism. Terpenes are photosynthetic pigments, electron carriers, plant growth regulators, are part of cell membranes, and participate in protein glycosylation in the central metabolism [24, 26]. They combine as defense chemicals, poisonous substances, and food deterrents in the secondary metabolism of insects [1].

1.5 Saponins

Saponins, glycosides extensively distributed in plants, are a varied group of molecules that includes a triterpenoid or steroidal aglycone with one or more sugar chains [27]. Because their immune-enhancing qualities have been utilized as adjuvants in vaccine formulations since the 1950s [28]. Ginseng dammarane sapogenins’ chemopreventive and chemotherapeutic properties have encouraged the creation of anticancer medicines at various stages of development [29]. Maturation inhibitors are novel HIV medicines researched using betulinic acid derivatives [30]. Inflammation, infection, alcoholism, pre- and postmenopausal symptoms, cerebrovascular and cardiovascular diseases such as hypertension and coronary heart disease, prophylaxis, and dementia, ultraviolet damage including cataract, gastric ulcer, gastritis, and duodenal ulcer have all been treated with saponin-containing pharmaceutical compositions or plant extracts [27, 30, 31]. Saponins have also been patented for use as adjuvants to improve the absorption of bioactive chemicals and medications [32]. Plants that contain saponins, such as yucca, ginseng, chestnut, licorice, and sarsaparilla, have been utilized in traditional medicine for ages to prevent and treat various disorders by numerous cultures [31].

1.6 Tannins

Tannins are phenolic chemicals that are found practically everywhere in plants. Fruit, the bark of trees, wood, and as well as in numerous wild plants and herbs, and forestry and agriculture [33], contain them. Chestnut tannin, is a renowned member of the commercial hydrolyzable tannins family, has been recommended as an antibacterial or a way to reduce mycotoxins [34]. Other uses for tannins, including ellagitannins and gallotannins, include treating bacterial infections, regulating cytotoxins production, antihistamine, antiasthma, and avoiding rhinitis, as well as blocking HIV propagation in human cells [33, 35]. There have also been reports on the usefulness of several tannin-derived chemicals in treating obesity, arteriosclerosis, and thrombosis, decreasing triglycerides, preventing Staphylococcus aureus and other gram-positive bacteria, and leukemia [33]. Patents have also been published on the non-commercial use of tannins to treat cognitive, neurological, and metabolic diseases, diabetes II and obesity, hypertension, and hypercholesterolemia [35]. Acacia mearnsii and Acacia nilotica tannins are among the condensed tannins. Both claim that tannins have antipyretic properties, with the first claiming antidiarrheic properties [36, 37]. Above the typical anthelmintic activity of tannins, Quebracho wood commercial tannin from Argentina also has anthelmintic activity. Sumac tannins, a combined condensed and hydrolyzable tannin have been suggested to possess anti-inflammatory, antimicrobial, and immunomodulatory potentials [33, 35]. Extensive applications for the cure of blood pressure, hypertension, and, most notably, hemorrhoidal disorders have been commercially available.

1.7 Lignans

The word “Lignan” refers to a class of dimeric phenylpropanoids containing two C6-C3 phenylpropanoids are linked by a C8 phenylpropanol. Lignans can be found in over 60 different types of vascular foliage. Lignans are a nonflavonoid polyphenol subclass [38]. They have high functional importance, and eating a diet rich in them can lower your risk of cardiovascular disease. Lignans can be found in barley, flaxseed, wheat bran, almonds, legumes, sesame seeds, fruits, and vegetables. A 12-year study published in 1889 found that those with elevated enterolactone levels had a decreased incidence of heart failure compared with low levels [39]. Clinical trials have demonstrated that adding diets with 30–50 grams of flaxseed per day for 4–12 weeks reduced LDL cholesterol by 8%–14% [40]. Another possible study looked at the influence of dietary lignan on breast cancer risk; women who consumed dietary lignan had a 17% minor risk of breast cancer than those in the lowest quartile [41]. According to the study report, women who consume many dietary lignans have a lower risk of endometrial cancer. Enterodiol and enterolactone have been shown to reduce the risk of hormone-related cancers [42]. Lignans are hypotensive, anticarcinogenic, cardiac-protective, lower cholesterol, and lengthen the food’s time in the stomach [43]. Because lignans have antioxidant properties, they can reduce oxidative stress and reduce the risk of diabetes-I. In type II diabetes, it can also block the phosphoenolpyruvate carboxykinase, which activates glucogenesis in the liver [44]. For decades, silymarin has been used to cure liver, spleen, and gallbladder illnesses. Hepatoprotective, antioxidant, anti-inflammatory, anticarcinogenic, and antidiabetic activities are found in silymarin [45].

1.8 Hydroxybenzoic acid

In the last ten years, at least three decades, hydroxybenzoic acids have been shown to have biological activity among the diversity of natural phenolic acids. Grapefruit, olive oil, and medlar fruit are all sources of 3-hydroxybenzoic acid [46]. It’s a glycosylating enzyme [47]. Carrots, oil palm, grapes, and various other plants have been shown to contain p-hydroxybenzoic acid, including satinwood, peroba, yellow-leaf tree, taheebo, southern catalpa, red sandalwood, chinese chaste tree, betel palm, cuban royal palm, and medlar [46]. Antifungal, antimutagenic, antisickling, estrogenic, and antibacterial properties have been discovered. The freshwater green alga responds to p-Hydroxybenzoic acid by growing faster [48, 49].

Khadem and Marles [46] have summarized the pharmaceutical activities of different hydroxybenzoic acids as mentioned in the following. Pyrocatechuic acid is a radical scavenger, a siderophore, and an antioxidant. Gentisic acid reduces LDL oxidation in humans and is an anti-inflammatory, analgesic, antiarthritic, antirheumatic, and cytostatic drug. Resorcylic acid is a nematicidal substance. For dandruff, ichthyosis, acne, psoriasis, and other skin disorders, salicylic acid has anti-inflammatory, keratolytic, antipyretic, antiseptic, analgesic, and antifungal characteristics. It acts as a hormonal modulator of plant tolerance to disease assaults and environmental stress. 6-Methylsalicylic acid is a toxin found in plants. It works as an antimicrobial and antifeeding agent. Thyroid peroxidase is inhibited by -resorcylic acid. Orsellinic acid has antibacterial properties. Antifungal, anti-inflammatory, antihepatotoxic, antioxidant, cytotoxic, free radical scavenger, apoptotic, chemopreventive, neuroprotective, platelet aggregation inhibitor, and LDL oxidation inhibitor are some of the bioactivities of protocatechuic acid. In addition to its antisickling and anthelmintic properties, vanillic acid has been shown to reduce hepatic fibrosis during liver injury. It’s also reported to be a 5′-nucleotidase inhibitor in snake venom. Antibacterial and antioxidant properties are found in isovanillic acid. Syringic acid possesses antibacterial and hepatoprotective properties in addition to being an antioxidant. Digallic acid is cytotoxic and anti-apoptotic. It has antigenotoxic and antioxidant properties as well. For lower plants, it has growth inhibitory and dormancy-inducing properties. Lunularic acid also exhibits antifungal, antialgicidal, and antihyaluronidase properties. Hydrangeic acid has anti-diabetic properties, lowering blood sugar, triglyceride, and free fatty acid levels. Anacardic acid is effective against the larvae of the Colorado potato beetle (Leptinotarsa decemlineata).

Anti-Helicobacter pylori action has been discovered in an anacardic acid combination. Ginkgolic acid suppresses protein SUMOylation in addition to its anticancer and antitubercular properties. SUMO proteins (small ubiquitin-related modifier proteins) regulate various cellular activities linked to cancer and neurological illnesses. Turgorins are thought to be chemicals that regulate thigmotactic and nyctinastic leaf movement. Current research has discovered that plant hormones do not control nyctinastic leaf movement but rather compounds that differ depending on the plant species. Platensimycin is a gram-positive bacterium (MRSA) inhibitor that inhibits cellular lipid production. Cannabidiolic acid inhibits cyclooxygenase-2 selectively and has antiproliferative properties. Cajaninstilbene acid contains anti-triglyceride and anti-glycemic properties. Cajaninstilbene acid, in addition to being an antioxidant, may be helpful for postmenopausal osteoporosis. It also had impermeability, anti-inflammatory, and analgesic properties [46, 47, 48, 49].

1.9 Gallic acid

Tallow-tree, the mangosteen related bridelia, garcinia densivenia, sappanwood, cinnabar ebony, elephant-apple, peroba, guava, water-berry, staghorn sumac, tamarisk, grape, witch-hazel, and red toon all contain gallic acid [46]. It’s been used as a styptic and astringent. Gallic acid has antineoplastic and bacteriostatic effects and is antimelanogenic and antioxidant [50]. Evening primrose phenolic fractions containing gallic acid demonstrated antitumor efficacy. It is reported for anticancer effects [51]. Gallic acid is also thought to have the anti-angiogenic properties of sweet leaf tea extract. In the mammalian intestine, gallic acid inhibits sucrase and some disaccharidases. As an anti-HSV-2 agent, Gallic acid showed promise [52]. It inhibits cell survival, invasion, proliferation, and angiogenesis of glioma cells, making it a potential treatment for brain tumors. On the other hand, Tannins have cytotoxic effects on cells other than tumor cells. Apoptosis and necrosis were used to kill Gallic acid-mediated cervical cancer cells [53]. Many gallic acid derivatives have antioxidant and antibacterial properties in nature [46].

1.10 Ellagic acid

Ellagic acid is a polyphenol extractive (tannin) present in various dicotyledons. Ellagic acid is mainly found as ester-linked with sugars in the composition of tannins, which are secondary metabolites in higher plants [54]. The authors note the principal active component for ellagic acid’s considerable antioxidant, anti-inflammatory, and gastroprotective activities [55]. Furthermore, ellagic acid’s involvement in the GABAergic system, inhibition of acetylcholinesterase, aldose reductase, suppression of proinflammatory markers, protein tyrosine phosphatases, and interaction with the serotonergic and adrenergic systems offer a solid basis for potential advances in the treatment of a variety of medical complications [55, 56]. Recent research suggests that ellagic acid can operate as an acetylcholinesterase inhibitor, raising acetylcholine levels in the brain. As a result, there is the potential to partially mitigate or repair cognitive dysfunctions in neurodegenerative diseases like Alzheimer’s [57]. Lastly, one of the ellagic acid’s most well-known effects, melanogenesis suppression, has been linked to the antioxidant properties of the compound [58]. Ellagic acid and its derivatives can be used in the supplement and functional food industries because of its anti-inflammatory properties in different cell systems. The development of medications necessitates additional investigation since delivery mechanisms will largely determine ellagic acid bioavailability [59].

1.11 Stilbenes

Stilbenes are phenylpropanoids with a 1,2-diphenylethylene backbone belonging to a small phenylpropanoid category. Transresveratrol is the fundamental unit of most plant stilbenes [60]. Stilbenes are natural antifungal, antiviral, antibacterial, antifungal, and antiviral; they have been demonstrated to have anti-inflammatory characteristics, estrogen receptor agonist properties, and impacts on cell proliferation, cell signaling pathways, and apoptosis [61, 62]. The majority of natural stilbenes are in the trans form. Resveratrol is the only stilbene that has been thoroughly researched and found to have potent anticancer, anti-inflammatory, and antioxidant properties. Pterostilbene has been demonstrated to have anti-diabetic characteristics [63]. Antitubulin properties have been reported for combretastatin [64]. Rhapontigenin has strong inhibitory potential on histamine release, responsible for various allergic reactions. In vitro, resveratrol and rhaponticin can prevent platelet aggregation [65].

1.12 Hydroxycinnamic Acids

The most extensive family of hydroxycinnamic acids comprises phenylalanine and tyrosine and has three-carbon side chains, e.g., p-coumaric, ferulic, caffeic, and sinapic acids. Hydroxycinnamic acids can also be found as amides and esters. Although these forms have been described for industrial and biological potential, there is no evidence to support their use as cosmeceutical components [66]. They have various physiological effects, including anti-inflammatory, antioxidant, antibacterial, anti-melanogenic, and anti-collagenase activity, which drive a surge in using hydroxycinnamic acids in skincare formulations. Antioxidant, antibacterial, anticancer, anti-inflammatory, antiplatelet aggregation, and other intriguing health effects have been discovered on coumaric acid and its derivatives [24]. Caffeic acid is produced via coumaric acid’s hydroxylation and possesses anticancer, anti-inflammatory, antibacterial, and antidiabetic effects [67]. Ferulic acid has shown antioxidant, anticancer, UV-absorbing, and anti-inflammatory effects, and it is now being used in cosmetic emulsions for topical application [9]. Antioxidant, anticancer, anti-inflammatory, and antibacterial activities of rosmarinic acid have been discovered [68]. Numerous studies have shown anti-inflammatory, antidiabetic, antiviral, antioxidant, and anti-tyrosinase properties of chlorogenic acid [69]. Fruits and vegetables also contain sinapic acid [70].

1.13 Curcuminoids

Curcuminoids are phenolic chemicals used for spice, color, culinary additives, and medicinal agents. Curcuminoids have exhibited various pharmaceutical effects in preclinical cell culture and animal investigations, including antioxidant, neuroprotective, anticancer, anti-inflammatory, anti-acidogenic, radioprotective, and arthritis [71]. Curcuminoids have also been shown to have a potential therapeutic effect in various chronic disorders, including colon, lung, breast cancer, and inflammatory bowel disease [72]. Ex vivo AChE assay revealed dose-dependent inhibition of curcuminoids and their components in the frontal brain and hippocampus. In scopolamine-induced amnesia, their effect on memory was prominent and was comparable in memory-enhancing impact [73].

Curcuminoids have shown significant antioxidant activity in several in vitro and in vivo studies. They can help individuals with b-thalassemia/Hb E disease reduce oxidative damage. Curcuminoids are antioxidative polyphenols with radiomodulatory characteristics, which allow them to protect non-cancerous cells while radiosensitizing tumor cells [74]. Human cancer cell lines were used to test the antiproliferative effects of curcuminoids and two turmerones substances derived from the rhizome of C. longa. Curcuminoids and turmerone both reduced cancer cell proliferation in a dose-dependent manner. Curcuminoids, turmerone, and Arturmerone’s immunomodulatory effects highlighted the potential for curcuminoids and turmerones to be used as chemopreventive agents [75]. Turmeric’s curcuminoids and other vital components inhibited the virulence features of Streptococcus mutants’ biofilms, for example, bacterial adhesion, acidogenicity, and aciduricity, without killing the target bacteria. These substances can be used to prevent the production of dental biofilms and, as a result, dental caries. Aqeel et al. [76] evaluated the antiacanthamoebic potential of resveratrol and curcuminoids utilizing adhesion and cytotoxicity experiments using primary human brain microvascular endothelial cells, which contribute to the blood-brain barrier. Amoeba binding was reduced by 57% and 73%, respectively, when organisms were pre-exposed to 100 mg resveratrol and DMC, whereas cytotoxicity of host cells was decreased by 86%. According to the findings, resveratrol and DMC have potent anti-acanthamoeba properties [71].

2. Antioxidant activity of secondary metabolites

Secondary metabolites are organic compounds biosynthesized within an organism and not considered necessary for their growth, development, and reproduction. They are not involved in metabolic reactions and are considered neutral, especially in primary metabolic responses. However, they are generally regarded as the compounds of defense of an organism against environmental stresses and predators, signaling molecules, and involved in various molecular interactions like symbiosis, competition, and metal ions transport [77, 78]. They are engaged in improving health as many secondary metabolites act as antibiotics, anabolics, immunomodulators, and growth promoters. Some act as nutraceuticals, fighting against diseases (directly) and aiding the body to fight (indirectly). Some are pesticides, insecticides, and pheromones and displayed established health-promoting effects and significant roles as disease eradicators [79]. More than two million secondary metabolites are known to date, and they are generally classified into alkaloids, flavonoids, polyphenols, phytosterols, and terpenoids. However, McMurry [80] classified them into five main classes: terpenoids and steroids, fatty acid-derived substances and polyketides, alkaloids, nonribosomal polypeptides, and enzyme cofactors. Secondary metabolites are reported mainly from plants (80%). However, many bacterial, fungal, and aquatic organisms like corals, tunicates, snails, and sponges are also reported to contain these compounds [81].

The majority of the secondary metabolites are plant-based (especially tannins, terpenoids, alkaloids, and flavonoids) and represent many vital functions in medicines, culinary, cosmetics, tannery industry, etc. However, besides that, the data is scarce regarding the antioxidant activities of the pure secondary metabolites; some of the compounds that are proven antioxidants in nature are mentioned in Table 1.

Secondary metabolite	Category
Chrysin	Flavones
Apigenin
Naringin and Naringenin	Flavonones
Taxifolin
Eriodictyol
Hesperidin
Isosakuranetin
Quercetin	Flavonols
Kaempferol
Rutin
Astilbin	Flavononols
Engeletin
Genistin
Taxifolin
Daidzin and Daidzein	Isoflavones
Genistein
(+)-Catechin, (+)-Gallocatechin, (−)-Epicatechin and (−)-Epigallocatechin,	Flavanols
(−)-Epicatechin gallate and (−)-Epigallocatechin gallate
Cyanidin
Epigenidin	Anthocyanidins
Delphinium
Pelargonidin

Table 1.

Known natural secondary metabolites with proven antioxidant activities.

Source: Adapted and modified from Naczk and Shahidi [82]

As a result of metabolism, many free radicals are also generated within the living organisms’ bodies and are regarded as reactive oxygen species (ROS). These ROS cause oxidative damage to the bodies of living organisms, and the antioxidant species mitigate them by reducing oxidative damage. Hence, they are considered as the first line of defense. Peroxidases and metal chelating proteins help reduce oxidative stress damage together with free radical scavengers like vitamins C and E [83, 84]. There are a few examples of synthetic antioxidants which are used in industry. However, they are not believed to be safe, so the requirement for the antioxidants from natural sources increases, e.g., plants [85].

Naturally biosynthesized secondary metabolites with enormous antioxidant activity of phenolic nature include flavonoids, terpenes, phenolic acids, lignans, stilbenes, tocopherols, tannins, etc. these compounds are biosynthesized in plants having a strong antioxidant potential through which living organisms are somehow protected from various diseases [86]. Among secondary metabolites, alkaloids in an organism protect it from biotic stresses, and phenolics play a protective role against oxidative stresses being strong antioxidants. Plants can protect from UV radiation because they contain phenylpropanoids [87]. Polyphenolic compounds are considered a prime group responsible for antioxidant activities [88, 89].

The food consumed containing phenolic compounds displays an antioxidant role due to these antioxidant compounds (Figure 1) [90]. Terpenoids are a broad category of secondary metabolites regarded as strong antioxidants and used mostly in perfumery [91]. Stilbenes are phytoalexins biosynthesized in plants to overcome stresses are reported for antioxidant properties and resveratrol; for example, they are an active constituent of many medications. Isoflavones are polyphenolic biomolecules, biosynthesized in the Fabaceae family, especially in soybean in the form of glycosides, and exhibit antioxidant activities. Tannins are complex derivatives of phenolic acids, are found in many plant species, and are enormously effective antioxidants with promising cytotoxic and antiparasitic properties [92, 93].

Figure 1.

Phenolic antioxidants. Adapted from Shahidi and Ambigaipalan [85].

There are few antioxidants synthesized and allowed to be used in the food industry, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), octyl gallate (OG), propyl gallate (PG), dodecyl gallate (DG) and tertiary-butylhydroquinone (TBHQ) [94] to delay lipid oxidation and as processing agent of oils and fats [95].

3. Antimicrobial activity of secondary metabolites

Secondary metabolites include alkaloids, flavonoids, terpenoids, and other phenolic compounds; these molecules are linked to plant defense processes and protect against many diseases. Secondary metabolites are involved in antibacterial and antifungal activities [96].

3.1 Antibacterial properties of secondary metabolites

Bacterial infections are considered a significant public health problem worldwide. Bacterial infection can also occur due to multi-drug resistance, which leads to mortality and morbidity [97]. For that reason, antibiotic resistance has become a global concern. The increase in the multi-drug resistance of bacteria threatens the therapeutic efficacy of several drugs. Using different solvent systems, numerous researchers have studied plants’ antibacterial activities of leaves, flowers, stems, roots, and fruits [98]. Therefore, new antibacterial drugs are needed to treat various diseases with low toxicity and less price. For that purpose, secondary metabolites from plants are currently considered to develop new drugs because they are rich in natural compounds.

Gallic acid and its derivatives are potential antibacterial agents that reduce bacterial diseases. Gallic acid and methyl gallate have shown significant antibacterial activity against Salmonella [99]. Phenolic compounds such as stilbenes, tannins, and isoflavones inhibited the growth of Bacillus and E. coli bacteria [100, 101]. Anacardic acid analogs extracted from the A. Ovest with various side chains exhibited antibacterial activity against S. aureus and S. pyogenes. On the other hand, alkaloids are used as scaffolding substructures in other antibacterial drugs, such as linezolid and trimethoprim. The alkaloid cocsoline from Epinetrumvillosum has broad antibacterial activity by inhibiting Shigella, Campylobacter jejuni, and C. coli stains [102, 103]. Squalamine, a polyamine alkaloid extracted from the tissue of the squalus shark acanthosis, revealed broad-spectrum steroidal antibiotic with potent bactericidal properties against both gram-positive and gram-negative bacterial stains [104]. Other alkaloids such as solanine, solasodine, and B-solamarine were isolated from Solanum dulcamara L. have shown antibacterial activity against S. aureus [97]. Bis-indole alkaloids from marine invertebrates have demonstrated antibacterial activity against S. aureus and methicillin-resistant S. aureus (MRSA) [105]. Berberine and hydrastine alkaloids were isolated from Goldenseal have been showing substantial antibacterial activity, particularly against S. pyogenes and S. aureus [106]. Cocsoline alkaloid isolated from Epinetrumvillosum (Exell) possesses antibacterial activity against Shigella strains, Campylobacter jejuni, and C. coli [107]. Tetrahydroanthraquinones are also exhibiting antibacterial activity. Pseudomonas aeruginosa and other gram-positive bacteria were suppressed by Altersolanols A–C and E. The antibacterial activity of tetrahydroanthraquinones is due to the presence of the hydroxy group at the C-5 position [108]. Coniothranthraquinone 1 has demonstrated antibacterial activity against S. aureus, while trichodermaquinone had antibacterial activity against MRSA [109, 110]. Deoxybostrycin and bostrycin have significant antibacterial properties against S. aureus, E. coli, Pseudomonas aeruginosa, Sarcina ventriculi, and Bacillus subtilis [111].

3.2 Antifungal properties

Resistance to antifungal drugs has been spread in recent years. Resistance to antifungal drugs has led to increased morbidity and mortality. Since the molecular mechanisms in humans and fungi are so similar, there is always the possibility that the fungal cytotoxic agent is toxic to host cells. As a result, patients with compromised immune systems, such as transplants, cancer patients, and diabetics, who do not respond effectively to current antifungal treatments, need new antifungal therapies. Antifungal drugs currently used to treat fungal infections have significant side effects such as itching, diarrhea, vomiting, etc. In addition, it is less effective because of the development of drug resistance by the many fungi [112, 113]. The alkaloids protoberberine jatrorrhizine, isolated from Mahonia aquifolium, were the most potent inhibitory antifungal activity [114]. (+)-Cocsoline is a bisbenzylisoquinoline alkaloid isolated from epinetrumvillosum whose antifungal action has been demonstrated [115]. The alkaloids N-ethylhydrasteinehydroxylactam and 1-methoxyberberine chloride isolated from Corydalis longipes have been shown to have significant inhibitory action [116]. Glaucium oxylobum produced four alkaloids: dicentrine, glaucine, protopine, and alpha-allocryptopin exhibited antifungal activity against Microsporumgypseum, Microsporumcanis, T. mentagrophytes, and Epidermophytonfloccosum [117]. Canthin-6-one and 5-methoxy-canthin-6-one from Zanthoxylumchiloperone var. angustifolium are antifungal against Candida albicans, Aspergillus fumigatus, and T. mentagrophytes [118]. Frangulanine, a cyclic peptide alkaloid, and waltherione A, quinolinone alkaloids derived from Melochiaodorata have been shown to antifungal activity against a wide range of pathogenic fungi [119]. Additionally, anodic alkali aninolinate has been shown to have antifungal action [120]. Two antimyctic fructoxin alkaloids have been identified from the root of Dictamnusdasycarpus. 3-Methoxisampangin from cleistopholispatens significantly inhibits C. albicans, A. fumigatus, and C. neoformans [121]. A new alkaloid, 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1-methylethyl pentanoate, was isolated from the plant Datura metel has shown in-vitro and in-vivo action against Aspergillus and Candida species [122]. Fungi toxic action was demonstrated for alkaloids isolated from Ruta graveolens L., Tomadini Glycoalkaloids isolated from tomatoes, cannabinoid alkaloid, isoquinoline, methaqualone, flavonol, and gallic acid [123, 124].

4. Anticancer potential of secondary metabolites

Cancer is the cause of death worldwide; experts are developing new therapies less likely to cause side effects. Cancer is one of the most severe health concerns, despite substantial advances in cancer therapy [125]. Several new secondary metabolites from plants are discovered each year, opening new avenues for research in the fight against cancer. Plant secondary metabolites have substantially contributed to this topic, which has been at the heart of herbal medicines. Plant’s secondary metabolites have been shown to have anticancer effects, such as the ability to reduce cancer cell growth and development, kill cancer cells, and fight against multi-drug resistance in certain malignancies [126]. Plant secondary metabolites are thought to be helpful in drug development. The secondary plant metabolites are presently used in clinical and undergoing clinical trials as anticancer therapies [127, 128].

For thousands of years, humans have used herbs to treat certain diseases. Researchers are particularly interested in generating anticancer drugs from the plant’s secondary metabolites. Plant secondary metabolites such as flavonoids, polyphenols, anthraquinones, triterpenoids, alkaloids, terpenoids, quinones, and others play an essential role in cancer prevention [129]. Flavonoids (6,7,30-trimethoxy-3,5,40-trihydroxy-flavone and 5,40-dihydroxy-3,6,30-trimethoxy-flavone 7-O- -d-glucoside) isolated from Chrysosplenium nudicaule Spearmary was reported as cytotoxic and antitumor activities in cancer cell growth of human leukemia and gastric cancer cell lines [130, 131]. The agathisflavone induces apoptosis and antiproliferative effect on the development of leukemia cells. Citrus flavonoids have a profound inhibitory effect on the development of leukemia cells. Other research suggests that quercetin may act as an antiproliferative agent by inhibiting cell proliferation, growth, and cell cycle termination [132, 133]. Studies of Kaempferol and quercetin have shown antiproliferative action by inhibiting the development of the human colon (HT-29, COLO 201, and LS-174T), breast (MCF-7 ADRr), and ovarian (OVCA 433) cancer cell lines [134, 135, 136]. In addition, quercetin inhibited the G1 phase of the cell cycle in human leukemic T-cells and human gastric cancer cells [137, 138]. In a human oral squamous carcinoma cell line (SCC-25), quercetin had a biphasic effect on cell growth and proliferation [139]. On the other hand, in-vivo research on quercetin has yielded consistent findings, indicating a promising chemopreventive drug against skin cancer [140]. In contrast, kaempferol treatment of the human lung cancer cell line A549 resulted in a dosage and time-dependent decrease in cell survival and DNA synthesis. While Kaempferol dramatically decreased the number of breast cancer cells (MCF-7) viable estrogen receptor-positive [141, 142].

Phenolic compounds are one of the most diverse and widespread groups of plant metabolites, and they have a wide range of biological roles in regulating carcinogenesis [143]. Polyphenols have several advantages as anticancer drugs, including high accessibility, minimal toxicity, and broad biological effects. The main advantage of polyphenols as anticancer drugs is cytotoxic effects on malignant cells growth [144, 145]. Many polyphenols have an anticancer effect in various cancer models, regardless of their different modes of action [146, 147]. Polyphenols of strawberries, including anthocyanins, Kaempferol, quercetin, coumaric acid esters, and ellagic acid esters, have been shown to inhibit the development of human oral and breast colon and prostate cancer cell lines [148]. The primary polyphenol of green tea, epigallocatechin-3-gallate (EGCG), is anticancer in various cancer types [149]. Researchers suggested that EGCG regulation may stimulate the production of reactive oxygen species and inhibit angiogenesis in cancer cells by regulating different pathways, such as AMP-activated protein kinase, epidermal growth factor receptor, insulin-like growth factor receptor, extracellular signal-regulated kinase, cyclin D1, Akt, STAT3, Wnt, and mTOR signaling in cancer cells [150, 151, 152]. A key ingredient of Plumbago zeylanica naphthoquinone has been shown in-vitro and in-vivo anticancer effective against various malignancies, including breast, pancreatic, lung, prostate, melanoma, and leukemia [153]. Cardanol, anacardic acid, and methyl cardol have been shown to decrease the cell growth of Hela cells and pituitary adenoma cells [154, 155]. In addition, anacardic acid-induced polymerase breakage, cell arrest, and regulation of apoptosis and anti-apoptotic proteins [156]. Furthermore, in-vivo investigations have confirmed plant-derived phenolic compounds’ anticancer activity [157]. Colon, lung, breast, liver, prostate, stomach, esophagus, small intestine, pancreas mammary gland, and skin cancers are using xenograft animal models [158]. In another study of cyanidin-3-glucoside (C3G), the major anthocyanin in blackberry was investigated for the inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanolyphorbol-13-acetate (TPA)-induced skin papillomas in an animal model [159]. Similarly, natural anthraquinones, such as rhein and emodin, have antitumor properties [160]. Tetrahydroanthraquinones, a kind of anthraquinone, inhibit cell proliferation, invasion, metastasis, and angiogenesis by apoptosis and cell cycle arrest. Altersolanol A (tetrahydroanthraquinone) has anticancer properties against bladder, colon, and stomach cancer. Moreover, Altersolanol A anticancer efficacy is linked to its pro-apoptotic and antiinvasive properties. A study reported that Altersolanol A has anticancer potential by reducing angiogenesis in-vitro and in-vivo [161, 162]. In addition, Altersolanol F reduced the viability of colorectal and cervical cancer cells, while Altersolanol N has cytotoxic effect against murine cancer cell line (L5178Y) [163, 164]. Likewise, several investigations have demonstrated catechins as antiproliferative properties in breast, colon, melanoma, and prostate cancer cells [165, 166, 167].

Isoquinoline alkaloid is a major alkaloid class with an anticancer effect in different cancer cells. Isoquinoline alkaloids are naturally isolated from the roots, and the bark of Coptis chinensis are important sources of [168]. Studies found that protoberberines (isoquinoline alkaloids) have significant anticancer potential in the treatment of gastric cancer [169]. Similarly, berberine alkaloid has been reported to have anticancer effects by suppressing the ERK/JNK/p38 MAPK/mTOR/p70 ribosomal S6 protein kinase and PI3K/Akt signaling pathways in cancer studies [170]. Tetrandrine (TET), a natural bis-benzylisoquinoline alkaloid, has shown anticancer activity against cancer cell lines. Tetrandrine-mediated cytotoxicity of chemotherapeutic drugs used to treat gastric cancer, including paclitaxel, 5-FU, oxaliplatin, and docetaxel [171, 172]. Piperlongumine, an amide alkaloid, has been shown anticancer by the intracellular ROS, p38/JNK signaling pathway [173, 174]. Hersutin alkaloid has been shown to induce apoptosis in HER2-positive and p53-mutated breast cancer cells [175]. Oxymatrine, a natural alkaloid isolated from the roots of Sophora chrysophylla, exhibits anticancer activity in human cervical cancer cells [176].

Terpenes are a broad category of secondary metabolites that include low polarity fragrant scaffolds and isoprene derivatives with various pharmacological activities, including anticancer activity. Triterpenoids have previously been shown to have anticancer properties in both in-vitro and in-vivo by nuclear factor-κβ (NF-κβ) and STAT3 signaling pathways [177]. The anticancer and narcotic activities of costunolide, a sesquiterpene lactone isolated from Saussurea lappa, have been demonstrated in gastrointestinal diseases [178]. Thymoquinone has been shown to slow the progression of diseases such as leukemia, breast adenocarcinoma, colorectal, pancreatic, prostate, and hepatic cancer [179]. The anticancer efficacy of thymoquinone against gastric cancer cells. Several other studies have shown that the combination of thymoquinone with 5-fluorouracil and cisplatin significantly improves the chemotherapeutic-induced anticancer effects in gastric cancer. Furthermore, thymoquinone has been shown to inhibit the Janus kinase (JAK)/STAT3 signaling pathway [180].

5. Conclusions

This study shows that plant cells produce a variety of compounds, mainly secondary metabolites, for defense mechanisms against bacteria, fungi, antioxidants, and cancer. Secondary metabolites with antibacterial, antifungal, antioxidant, and anticancer effects are sources of natural bioactive molecules, which control disease-causing pathogens in plants and humans. In addition, the different plant families have shown a unique combination of secondary metabolites; therefore, exhibiting different antibacterial, antifungal, antioxidant, and anticancer activities. The emerging research on identifying secondary metabolites is ongoing, and further research is encouraged to advance our knowledge about these compounds. Secondary metabolites can help treat infectious diseases that have increased resistance to current antibiotics. They can offer alternative medical therapy to individuals, particularly in developing nations where people may not access health care.

Acknowledgments

The authors are thankful to the Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan, for supporting this study. We also apologize to the authors of many exciting studies omitted due to limited information.

Conflict of interest

The authors declare that they have no conflict of interest.