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Bioactive Agents - Coggle Diagram

- - - - Catechins
        
        Epigallocatechin-3-gallate
        
        Epigallocatechin
  - - - Terpenoids
      - Tannins
      - Glycosides
  - - - Quercitin-3-D-galactoside
      - Kaempferol-3-glucoside
    - - Epicatechin
      - (-)-Epicatechin gallate
      - (-)-Epigallocatechin
      - Same as catechins?
    - - Theophiline
      - Caffeine
    - - (+)-Catechin (C)
      - (-)-Epicatechin (EC)
      - (-)-Epigallocatechin (EGC)
      - (-)-Epicatechin gallate (EGCG)
      - (-)Epigallocatechin gallate (ECG)
  - - - Catechins
        
        Catechins, the most reduced form of the C3 unit in flavonoid compounds, deserve special mention. These flavonoids have been extensively researched due to their occurrence in oolong green teas. It was noticed some time ago that teas exerted antimicrobial activity (227) and that they contain a mixture of catechin compounds. These compounds inhibited in vitro Vibrio cholerae O1 (25), Streptococcus mutans (23, 185, 186, 228), Shigella (235), and other bacteria and microorganisms (186, 224). The catechins inactivated cholera toxin in Vibrio (25) and inhibited isolated bacterial glucosyltransferases in S. mutans (151), possibly due to complexing activities described for quinones above. This latter activity was borne out in in vivo tests of conventional rats. When the rats were fed a diet containing 0.1% tea catechins, fissure caries (caused by S. mutans) was reduced by 40% (166).
      - Alkaloids
        
        Heterocyclic nitrogen compounds are called alkaloids. The first medically useful example of an alkaloid was morphine, isolated in 1805 from the opium poppy Papaver somniferum (69); the name morphine comes from the Greek Morpheus, god of dreams. Codeine and heroin are both derivatives of morphine. Diterpenoid alkaloids, commonly isolated from the plants of the Ranunculaceae, or buttercup (107) family (15), are commonly found to have antimicrobial properties (163). Solamargine, a glycoalkaloid from the berries of Solanum khasianum, and other alkaloids may be useful against HIV infection (142, 200) as well as intestinal infections associated with AIDS (140). While alkaloids have been found to have microbiocidal effects (including against Giardia and Entamoeba species [78]), the major antidiarrheal effect is probably due to their effects on transit time in the small intestine.
        Berberine is an important representative of the alkaloid group. It is potentially effective against trypanosomes (73) and plasmodia (163). The mechanism of action of highly aromatic planar quaternary alkaloids such as berberine and harmane (93) is attributed to their ability to intercalate with DNA (176).
    - - Catechins
        
        Catechins are the most reduced form of the C3 unit in flavonoid compounds and have been extensively researched due to their presence in oolong tea and other types of tea. These compounds have been shown to have antimicrobial action against Streptococcus mutans [25], Shigella [26], Vibrio [27] and other pathogenic bacteria [8].
      - Alkaloids
        
        Alkaloids exert considerable physiological effects on humans and animals and are used in therapeutics as narcotics and have a calming effect. Some alkaloids are strong poisons, for example, curare, which has the ability to paralyze the nervous system. Alkaloids are considered to be an insecticide defense means in plants. Some alkaloids, for example nicotine, play a role in enzymatic oxidation-reduction processes. The alkaloid-producing plants are dicotyledons, and to a lesser extent monocotyledons and cryptogamas. Generally, a plant contains several alkaloids. The alkaloid content depends on the age of the plant, region, climate and season. Algae and bryophytes do not produce alkaloids. They are rare in mushrooms (ergotamine), in pteridophytes (nicotine in Equisetum, coniine in Lycopodium spores) and in gymnosperms (ephedrine). In the angiosperms, some families are reputed by their high contents in alkaloids: Solanaceae (solanine, nicotine, hyoscyamine, atropine), Rubiaceae (caffeine, quinine), and Papaveraceae (morphine, papaverine, codeine, narceine, etc.). The most important alkaloids are: coniine, nicotine, tropane, atropine, cocaine, quinine, papaverine, morphine, codeine, strychnine, caffeine, and others [3,8]. Alkaloids have a great structural diversity and are synthesized mainly in Solanaceae and Fabaceae. For example, pepper (Capsicum annuum), contains alkamide alkaloids such as affinin (spilanthol) and capsaicin [33], potato (Solanum tuberosum) contains several toxic and teratogenic glycoalkaloids [34], and lupin (Lupinus angustifolius) contains a large number of quinolizidine alkaloids, notably 13 α-hydroxy lupanine and lupanine. Highly unsaturated planar quaternary alkaloids possess the ability to intercalate with DNA [8] and modify the nucleotide sequences [10]. Tamarindus indica (Fabaceae) aqueous pulp extract was found to have antimicrobial effect against E. coli, S. aureus, and P. aeruginosa, but not against Salmonella typhi [35]. Zapoteca portoricensis leaf extract has antibacterial action against Gram-positive bacteria S. aureus, E. coli, Streptococcus pyogenes, Klebsiella pneumoniae, and Gram-negative P. aeruginosa [35].
    - - Alkaloids
        
        Regarding the antibacterial activity of alkaloids, many studies through the years have shown that many of these compounds could play a role in the treatment of many infectious diseases. An alkaloid which exhibits antibacterial activity is sanguinarine. It has long been known that sanguinarine, a benzophenanthridine alkaloid derived from the rhizomes of Sanguinaria canadensis, has broad antimicrobial activity and anti-inflammatory properties. In fact, in vitro studies have shown that sanguinarine is able to inhibit bacterial adherence to the surface of teeth, exerting an anti-plaque action (Godowski, 1988, Hannah et al., 1989). This alkaloid exerts its antibacterial activity by perturbing bacterial FtsZ Z-ring formation and inhibiting bacterial cytokinesis (Beuria et al., 2005, Kelley et al., 2012). The Authors of two recent studies (Hamoud et al., 2014, Hamoud et al., 2015) tested a combination of sanguinarine, EDTA and vancomycin and a combination of sanguinarine, EDTA and streptomycin against gram-positive and gram-negative bacteria, including Multi-Drug Resistant (MDR) bacteria. The results of these studies showed that sanguinarine has strong activity against all the strains tested (Minimum Inhibitory Concentration (MIC): 0.5–128 μg/ml); additive and synergistic effects were recorded for all sanguinarine + EDTA and sanguinarine + EDTA + vancomycin associations against gram-negative bacteria. The combination of sanguinarine + EDTA + streptomycin also showed synergistic activity against almost all the strains with the exception of Methicillin Resistant Staphylococcus aureus (MRSA). Berberine, an isoquinoline-type alkaloid, contributes to oral health benefits. Several studies have demonstrated the efficacy of berberine against oral streptococcal growth and selected endodontic pathogens using a multispecies biofilm tooth model (Dziedzic et al., 2015, Xie et al., 2012). The most remarkable antibacterial effect was observed against Streptococcus sanguinis (MIC: 512 μg/ml) and the most significant synergistic effect was found in combination with penicillin, clindamycin and erythromycin (Dziedzic et al., 2015). Moreover Xie et al. (2012), demonstrated that berberine is more effective than saline as an endodontic irrigant against selected endodontic pathogens in vitro and, when combined with chlorhexidine 1%, is comparable with NaOCl in its bactericidal efficacy. In 2015 Kang et al. (2015), showed that berberine has an inhibitory effect on the growth of Actinobacillus pleuropneumoniae with a MIC value of 0.3125 mg/ml. Several studies (Boulanger et al.
        
        Alkaloids are organic nitrogenous bases. Their chemical structures are extremely variable. In 1819 the German chemist W. Meissner introduced the concept of alkaloids to indicate natural compounds which react as bases. These molecules have diverse and important physiological effects on humans and other animals. In the nineteenth century morphine was the first isolated alkaloid, derived from opium (Lesch, 1981), subsequently, two French researchers (P.J. Pelletier and J.B. Caventou) isolated other alkaloids including strychnine (1817), emetine (1817), brucine (1819), piperine (1819), caffeine (1819), quinine (1820), colchicine (1820) and coniine (1826). The latter compound was the first alkaloid to have its structure established (Schiff, 1870) and to be synthesized (Ladenburg, 1889). Alkaloids are produced by a large variety of organisms such as plants, bacteria, fungi and animals and have been used in medicine since ancient times. They have many effects including antimalarial (quinine), antiasthma (ephedrine), vasodilatator (vincamine), anti-hypertensive (reserpine), anti-tumor (vinblastine and vincristine) and anti-arrhythmic (quinidine) effects. Also alkaloids possess psychotropic and stimulant activities (cocaine, caffeine and nicotine) and can exert an analgesic effect, such as in morphine. Last, but not least, are the antibacterial and anti-virulence effects of alkaloids (Table 1).
    - - Catechins
        
        Hubera et al.42 have evidenced that polyphenolic compounds can interfere with bacterial quorum-sensing. Catechin-copper (II) complexes damage the cytoplasmic membrane of E. coli43,44. EGC is reported to bind to the ATP site of the DNA gyrase b subunit of bacteria and inhibit the activity of the gyrase enzyme43. The bactericidal action of catechin is due to its hydrogen peroxide generation44. The highest antimicrobial activity of tea is due to presence of catechins polyphenols which damage the bacterial cell membrane. In terms of antimicrobial acitivity, EGC and EGCG have been shown to exhibit highest antimicrobial effect. EGCG is the most established in terms of bactericidal activity. In Escherichia coli, EGCG induces the destruction of biofilms by damaging bacterial membranes and degrading exopolysaccharides (EPS)45. Sub-MIC levels of EGCG inhibit biofilm formation in ocular Staphylococcal isolates46 and periodontopathogenic bacterium Eikenella corrodens 47. Tea catechins, including EGCG, inhibit the growth of planktonic P. gingivalis.48.
- - - - Examples
        
        Protosappanin D
        
        Protosappanin E
        
        Haematoxylin
        
        Protosappanin A
        
        Brazilin
      - Action
        
        Plant Products as Antimicrobial Agents
        
        Flavones, flavonoids, and flavonols. Flavones are phenolic structures containing one carbonyl group (as opposed to the two carbonyls in quinones) (Fig. (Fig.1).1). The addition of a 3-hydroxyl group yields a flavonol (69). Flavonoids are also hydroxylated phenolic substances but occur as a C6-C3 unit linked to an aromatic ring. Since they are known to be synthesized by plants in response to microbial infection (56), it should not be surprising that they have been found in vitro to be effective antimicrobial substances against a wide array of microorganisms. Their activity is probably due to their ability to complex with extracellular and soluble proteins and to complex with bacterial cell walls, as described above for quinones. More lipophilic flavonoids may also disrupt microbial membranes (229).
        
        Catechins, the most reduced form of the C3 unit in flavonoid compounds, deserve special mention. These flavonoids have been extensively researched due to their occurrence in oolong green teas. It was noticed some time ago that teas exerted antimicrobial activity (227) and that they contain a mixture of catechin compounds. These compounds inhibited in vitro Vibrio cholerae O1 (25), Streptococcus mutans (23, 185, 186, 228), Shigella (235), and other bacteria and microorganisms (186, 224). The catechins inactivated cholera toxin in Vibrio (25) and inhibited isolated bacterial glucosyltransferases in S. mutans (151), possibly due to complexing activities described for quinones above. This latter activity was borne out in in vivo tests of conventional rats. When the rats were fed a diet containing 0.1% tea catechins, fissure caries (caused by S. mutans) was reduced by 40% (166).
        
        Antimicrobial compounds from plants
        
        Flavonoids are phenolic compounds found in land plants like bryophytes (hornworts, liverworts, mosses) and vascular plants (ferns, gymnosperms, angiosperms). They are synthesized in the cytoplasm of the plant cell and then accumulate in vacuoles that fuse with the central vacuole of epidermis and cortex cells. Flavonoids have a defensive function against insects, fungi and viruses, as well as against invading invertebrates.
        Chapter 10 252 The biological action of flavonoids is due to their ability to complex soluble and extracellular proteins and to bind to the bacterial cell wall. It has been shown that several lipophilic flavonoids may disrupt cell membranes [23,24] Flavones (Figure 4) are flavonoids having an unsaturated 3-C chain with a C2-C3 double bond, such as flavonols, which differ in the absence of a hydroxyl group at position 3. This minor difference in structure has major consequences in biosynthesis and the physiological role of the flavones in the cell. Flavones are found especially in vascular plants in which they form glycosides and aglycones
        
        Phytochemicals for human disease
        
        Flavonoids are a large group of compounds found in many fruits, vegetables and legumes. Many natural flavonoids have been reported as possessing various pharmacological properties, with potential utility in the chemoprevention of various diseases associated with oxidative stress, such as cancer, cardiovascular and neurodegenerative disease (Ferrazzano et al., 2011, Heim et al., 2002, Kuroda and Hara, 1999, Ramassamy, 2006). In addition to their antioxidant activity, flavonoids also show good antibacterial activity against both gram-positive and gram-negative isolates (Table 5) (Coppo and Marchese, 2014, Daglia, 2012) likely due to their ability to inhibit DNA gyrase, cell membrane function and bacterial energy metabolism (Cushnie and Lamb, 2005, Njume et al., 2009). DNA replication is one of the most basic biological functions and should be a prime target in antibiotic development. In recent years, flavonoids have been studied for their ability to interact with DNA helicases, proteins essential for DNA replication, repair, and recombination (Lohman et al., 2008), and to prevent dNTPs binding. In particular Chen and Huang (2011), studied 4 flavonoids (galangin, kaempferol, quercetin and myrecetin at 10 μM) capable of inhibiting the interaction of K. pneumoniae DnaB helicase with dNTPs, while Huang et al. (2015), demonstrated that some flavonoids (kaempferol and myrecetin, at 35 μM) inhibit the PriA helicase activity of S. aureus. Flavonoids can be further divided into six subfamilies on the basis of differences in their molecular backbone structure: flavonols, flavones, flavanols, flavanones, anthocyanidins and isoflavonoids.
        
        Polyphenols constitute a great portion of the phytochemicals found abundantly in fruits, vegetables, nuts, seeds, stems, flowers and beverages such as coffee, tea and red wine. In recent years dietary polyphenols have been successfully evaluated as chemopreventive and therapeutic agents thanks to their direct antimicrobial action and antibiotic modulation activity (Gibbons, 2005, Stermitz et al., 2000). To date more than 8000 phenolic structures have been studied and can be divided into many sub-groups according to their chemical structure, source of origin and biological functions. Regarding their chemical structure, polyphenols can be classified as flavonoids and non-flavonoids.
  - - - https://www.sciencedirect.com/science/article/abs/pii/S0378874103004409
      - https://www.sciencedirect.com/science/article/abs/pii/S2221169112601440
      - https://www.scopus.com/record/display.uri?eid=2-s2.0-4944225004&origin=inward&txGid=c6a48ab31af58c8216a0912a347c91cd
- - - - Berberine
      - Palmatine
      - Coptisine
      - Magnoflorine
      - Jatrorrhizine
      - Worenine
      - Columbamine
    - - Ferulic acid
  - - - The protein FtsZ is important in bacterial cell division, and it is the prokaryotic homolog of the eukaryotic tubulin. Berberine, an alkaloid, binds to FtsZ protein with high affinity, causing the inhibition of FtsZ assembly and its GTPase activity, leading to cell elongation, which causes inhibition of cell division (Boberek et al., 2010).
    - - Berberine is an important representative of the alkaloid group. It is potentially effective against trypanosomes (73) and plasmodia (163). The mechanism of action of highly aromatic planar quaternary alkaloids such as berberine and harmane (93) is attributed to their ability to intercalate with DNA (176).
- - - - Glycosides
        
        Glycyrrhizin
        
        Flavonoids
        
        Triterpenoids
    - - Glycosides
        
        Liquiritin
      - Flavonoids
        
        Liquiritin apioside
      - Chalcones
        
        Isoliquiritin apioside
        
        Isoliquiritin
      - Flavanone
        
        Liquiritigenin
  - - - Terpenoids
        
        The fragrance of plants is carried in the so called quinta essentia, or essential oil fraction. These oils are secondary metabolites that are highly enriched in compounds based on an isoprene structure (Fig. (Fig.1).1). They are called terpenes, their general chemical structure is C10H16, and they occur as diterpenes, triterpenes, and tetraterpenes (C20, C30, and C40), as well as hemiterpenes (C5) and sesquiterpenes (C15). When the compounds contain additional elements, usually oxygen, they are termed terpenoids.
        
        Terpenoids are synthesized from acetate units, and as such they share their origins with fatty acids. They differ from fatty acids in that they contain extensive branching and are cyclized. Examples of common terpenoids are methanol and camphor (monoterpenes) and farnesol and artemisin (sesquiterpenoids). Artemisin and its derivative α-arteether, also known by the name qinghaosu, find current use as antimalarials (237). In 1985, the steering committee of the scientific working group of the World Health Organization decided to develop the latter drug as a treatment for cerebral malaria.
        
        Terpenenes or terpenoids are active against bacteria (4, 8, 22, 82, 90, 121, 144, 197, 220, 221), fungi (18, 84, 122, 179, 180, 213, 221), viruses (74, 86, 173, 212, 246), and protozoa (78, 237). In 1977, it was reported that 60% of essential oil derivatives examined to date were inhibitory to fungi while 30% inhibited bacteria (39). The triterpenoid betulinic acid is just one of several terpenoids (see below) which have been shown to inhibit HIV. The mechanism of action of terpenes is not fully understood but is speculated to involve membrane disruption by the lipophilic compounds. Accordingly, Mendoza et al. (144) found that increasing the hydrophilicity of kaurene diterpenoids by addition of a methyl group drastically reduced their antimicrobial activity. Food scientists have found the terpenoids present in essential oils of plants to be useful in the control of Listeria monocytogenes (16). Oil of basil, a commercially available herbal, was found to be as effective as 125 ppm chlorine in disinfecting lettuce leaves (241).
        
        Chile peppers are a food item found nearly ubiquitously in many Mesoamerican cultures (44). Their use may reflect more than a desire to flavor foods. Many essential nutrients, such as vitamin C, provitamins A and E, and several B vitamins, are found in chiles (27). A terpenoid constituent, capsaicin, has a wide range of biological activities in humans, affecting the nervous, cardiovascular, and digestive systems (236) as well as finding use as an analgesic (47). The evidence for its antimicrobial activity is mixed. Recently, Cichewicz and Thorpe (42) found that capsaicin might enhance the growth of Candida albicans but that it clearly inhibited various bacteria to differing extents. Although possibly detrimental to the human gastric mucosa, capsaicin is also bactericidal to Helicobacter pylori (106). Another hot-tasting diterpene, aframodial, from a Cameroonian spice, is a broad-spectrum antifungal (18).
        
        The ethanol-soluble fraction of purple prairie clover yields a terpenoid called petalostemumol, which showed excellent activity against Bacillus subtilis and Staphylococcus aureus and lesser activity against gram-negative bacteria as well as Candida albicans (100). Two diterpenes isolated by Batista et al. (23) were found to be more democratic; they worked well against Staphylococcus aureus, V. cholerae, P. aeruginosa, and Candida spp. When it was observed that residents of Mali used the bark of a tree called Ptelopsis suberosa for the treatment of gastric ulcers, investigators tested terpenoid-containing fractions in 10 rats before and after the rats had ulcers chemically induced. They found that the terpenoids prevented the formation of ulcers and diminished the severity of existent ulcers. Whether this activity was due to antimicrobial action or to protection of the gastric mucosa is not clear (53). Kadota et al. (108) found that trichorabdal A, a diterpene from a Japanese herb, could directly inhibit H. pylori.
    - - Glycosides
        
        Glycosides are organic compounds in which a sugar is bound to another functional group through a glycosidic bond (Figure 7). According to the type of aglycone, glycosides are classified in phenolic glycosides and cyanogenic glycosides (aglycone represented by a cyanide group). In many plants chemicals are in the form of inactive glycosides, which can be activated by enzyme hydrolysis. An important group of glycosides are the glucosinolates, the precursors of isothiocyanates, found in 16 dicotyledonous families [10]. Glucosinolates are secondary metabolites that contain sulphur and nitrogen, mainly found in the Brassicaceae family. Sinigrin is present in broccoli, mustard and Brussels sprouts and is reported to have antifungal, antimicrobial, anticancer, antioxidant and anti-inflammatory activity. Lobularia libyca produces glucosinolates such as glucoiberverine, glucoiberin and glucoerucin with antimicrobial activity against C. albicans and P. aeruginosa [2]
    - - Triterpenes
        
        The triterpenes, another group of terpenoids, consist of six isoprene units. Oleanolic acid is a triterpenoid compound endowed with antibacterial activity against many bacteria. It was able to inhibit the growth of M. tuberculosis, including drugs-susceptible strains (susceptible to the first-line anti-tuberculosis drugs: rifampicin, isoniazid and ethambutol) with MICs values of 50–100 μg/ml and drug-resistant isolates with MIC values of 100–200 50–100 μg/ml. In addition, the combination of oleanolic acid with rifampicin, isoniazide and ethambutol showed synergistic antibacterial effects against drug-resistant strains. The MIC values of oleanolic acid were significantly decreased in combination with isonizide, rifampicin and ethambutol (MIC value reductions ranging from 4 fold to 32 fold, 16 fold to 128 fold and from 16 fold to 128 fold, respectively). In 2011, three new triterpenoids (bonianic acid A and B and 3-O-acetyluncaric acid) were isolated from Radermachera boniana with six known molecules, including ursolic acid, oleanolic acid and ergosterol peroxide, and were tested against M. tuberculosis (Truong et al., 2011). Ergosterol peroxide was the most active compound against this pathogen followed by bonianic acids B and A (MIC values of 3.5 μM, 9.9 μM and 34.8 μM, respectively). Other compounds showed less or no activity. The mixture of ursolic and oleanolic acids was also found to have synergistic effects against M. tuberculosis (Jiménez-Arellanes et al., 2013). Another study (Cunha et al., 2010) evaluated the antibacterial activity of oleanolic acid and ursolic acid (another triterpenoid compound) extracted from Miconia ligustroides against Bacillus cereus, Vibrio cholerae, S. choleraesuis, K. pneumoniae and S. pneumoniae. Ursolic acid was active against B. cereus (MICs value of 20 μg/ml), while oleanolic acid was active against both B. cereus and S. pneumoniae (MICs values of 80 μg/ml for both strains). The union of the two compounds did not enhance the antibacterial effect. Ursolic acid and oleanolic acid were found to be active against planktonic cariogenic microorganisms and their biofilm (Zhou et al., 2013). In 2014 a research group (Zou et al., 2014) evaluated the synergistic effect of ursolic acid and xylitol against oral biofilms produced by S. mutans and S. sobrinus. The MICs of ursolic acid ranged from 128 to 256 μg/ml while the MICs of xylitol were 20% for all tested bacteria. The synergistic interaction of the two compounds was observed against all tested microorganisms (Fractional Inhibitory Concentrations: FICs < 1). Oleanolic and ursolic acids were able to affect the virulence factors of L. monocytogenes, inhibiting listeriolysin O activity without influencing toxin secretion and reducing the capacity of these bacteria to form biofilms (Kurek et al., 2010). In 2014 Chung et al. (2014), isolated and identified three known triterpenoids (α-amyrin, betulinic acid and betulinaldehyde) from the bark of Calliparca farinosa Roxb.; these molecules showed antimicrobial activity against both MRSA and MSSA (MICs values ranged from 2 to 512 μg/ml) and could represent an alternative to circumvent antibiotic resistance in S. aureus.
    - - The results of the present study indicate that the purified flavonoid glycosides from G. glandulosum possess antimicrobial activities. Their mode of antibacterial activity is due to cell lysis and disruption of the cytoplasmic membrane by action upon the membrane permeability leading to leakage of cellular components and eventually cell death. This will lead to improve antimicrobial formulations and to ensure the prevention of the emergence of microbial resistance. However, the possibility remains that sites of action other than the cytoplasmic membrane exist. Further work is required to expatiate fully the mechanisms involved.