Therapeutic Insights into Herbal Medicine through the Use of Phytomolecules

Pharmacological Potential of Bioactive Phloroglucinol Compounds of the Plant Kingdom

Yvan Anderson Tchangoue Ngandjui¹, *, Niranjan Das², Subhash C. Mandal³, Simeon Fogue Kouam¹

¹ Department of Chemistry, Higher Teacher Training College, University of Yaounde, Yaounde, Cameroon

² Department of Chemistry, Iswar Chandra Vidyasagar College, Belonia-799155, Tripura, India

³ Pharmacognosy and Phytotherapy Research Laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700032, India

Abstract

Historically, natural products, which are substances generated by living organisms found in nature, have made an important contribution to pharmacotherapy, especially those from plant sources. Phloroglucinols are significant bioactive polyphenolic compounds that are found in plants, marine and microbial sources. Their chemical structures include an aromatic phenyl ring with three hydroxyl groups and are usually made of two or more rings linked together through methylene bridges. They exist widely in several plant families and are known for their significant biological potentials, such as antibacterial, antifungal, anti-inflammatory, antileishmanial, antiplasmodial, antiproliferative and cytotoxicity activities. This book chapter provides an overview of phloroglucinol compounds in the world, their location in the plant, and their pharmacological applications.

Keywords: Biological activity, Medicinal plants, Natural products, Phloroglucinols, Phytomedicine.

* Corresponding author Yvan Anderson Tchangoue Ngandjui: Department of Chemistry, Higher Teacher Training College, University of Yaounde, Yaounde, Cameroon; E-mail: [email protected]

INTRODUCTION

Since time immemorial, mankind has searched for medicines to prevent and cure various diseases and also to get rid of pain. These medicines are generally compounds derived from natural resources such as animals, marine organisms, microorganisms, or plants. Among these sources, plants have been broadly recognized as a tremendous source of medicinal compounds for the preparation of drugs [1].

According to the World Health Organization, up to 80% of the world's population continue to depend on plants for their medicinal properties [2, 3]. Plants have different chemical compounds, including secondary metabolites, which are found in many families of the plant kingdom, and have been reported to possess several biological properties with various applications in industries, such as pharmaceutical industries [4-6]. Phloroglucinol derivatives, mostly found in the Myrtaceae family, are of interest because of their scaffolding structure and biological activities. The literature review indicates 700 naturally occurring phloroglucinols, including synthetic or semi-synthetic ones with a vast array of activities. Phloroglucinol Mylan and Spasfon are used worldwide as antispasmodic drugs that fight against abnormal and painful contractions [7].

Knowledge of these natural compounds in regard of their interesting activities can greatly contribute to the success of natural medicine management today and in the future.

In this chapter, we present what phloroglucinols are and the bioactive phloroglucinol compounds studied for their phytopharmacological potential. We also review the classes of phloroglucinols and their localization in the plant.

OVERVIEW OF PHLOROGLUCINOL COMPOUNDS

Definition

Phloroglucinol is a class of natural products containing 1,3,5-trihydroxy benzene (1) as the basic skeleton and the simplest member (Fig. 1). It is a colorless and odorless solid which was first isolated as a hydrolysis product of glucoside phloretin obtained from the bark of fruit trees. The phloroglucinol family, displays a large range of interesting biological activities and consists of more than 700 naturally occurring derivatives [8].

Fig. (1))

Chemical structure of 1,3,5-trihydroxy benzene.

Phloroglucinol as a Scaffold in Biology

Among the natural products, we have phloroglucinols, which are found in the form of derivatives such as anthocyanidins, catechins, coumarins, flavones, and glucosides. Some of these natural products have very interesting bioactivities and potential medical applications, as described in the next title [7].

Phloroglucinol Derivatives

Bioactive phloroglucinol compounds have been reported from diverse natural sources such as marine, microorganisms and plants. Phloroglucinol derivatives are a main class of secondary metabolites that we find in the Myrtaceae family as well as in several other families. In this book chapter, we have classified phloroglucinols into:

Monomeric,

Dimeric,

Trimeric,

Tetrameric and higher,

Phlorotannins.

We will particularly extend our chapter on monomeric and dimeric phloroglucinols [7].

Monomeric Phloroglucinols

Numerous monomeric phloroglucinols are reported to be present in plants as well as other natural sources and have been revealed to have several biological activities. Acyl phloroglucinols, phloroglucinol–terpene adducts, phloroglucinol glycosides, halogenated phloroglucinols, prenylated/geranylated phloroglucinols, phloroglucinols linked to an α -pyrone ring and cyclic polyketides are the different subclasses of the phloroglucinols. We will partially discuss these subclasses in the following sections.

Acyl Phloroglucinols

Among the number of acyl phloroglucinols which exist, only simple ones have been described, such as acyl phloroglucinols with a prenyl/geranyl moiety or with a pyran/furan ring skeleton, phloroglucinol terpene adducts and dimeric/trimeric acyl phloroglucinols Fig. (2). Acyl phloroglucinols are reviewed according to the variation in acyl functionalities, and the most known is grandinol (2), which is a phloroglucinol derivative obtained from mature leaves of Eucalyptus grandis and containing isovaleryl, formyl and methyl substituents [9].

Fig. (2))

Chemical structures of acyl phloroglucinols 2-6.

Another related acyl phloroglucinol compound was jensenone (3) isolated from Eucalyptus jensenii, where the methyl group of grandinol is replaced by a formyl group. Grandinol and jensenone are the precursors of biologically active phloroglucinols such as euglobals, grandinal, macrocarpals and sideroxylonals [10].

From natural sources, numerous phloroacetophenone equivalents have been reported. These comprise mallophenone (4) isolated from Mallotus japonicus, bancroftinone (5) obtained from essential oils of Eugenia caryophyllus, and methylxanthoxylin (6) from Melicope borbonica [11-13].

Phloroglucinol–terpene Adducts

Adducts Involving Chroman Ring Formation

In numerous species of Eucalyptus, euglobals constitute the largest group of phloroglucinol–terpene adducts and are diformyl or formyl–isovaleryl phloroglucinol–monoterpene or phloroglucinol–sesquiterpene adducts. Euglobal III (7), the first-reported euglobal, was obtained from Eucalyptus globulus Labill [14]. Robustadials A (8) and B (9), which also possess a moiety comparable to that of euglobals, were reported from Eucalyptus robusta as antimalarial compounds (Fig. 3) [15].

Fig. (3))

Chemical structures of a few phloroglucinol-terpene adducts (7-9).

Adducts without Chroman Ring Formation

Macrocarpals are among phloroglucinol–terpene adducts without chroman ring formation, and the first reported was macrocarpal A (10) from E. macrocarpa [15]. The structure of macrocarpal A (10) with a diformyl-isopentyl phloroglucinol skeleton joined to the sesquiterpene globulol has been established by X-ray and spectral analysis. After this, five other similar compounds known as macrocarpals B–E (11–14) and macrocarpal G (15) have been isolated [16]. Macrocarpals A (10) and B (11) are stereoisomers at C-9, while macrocarpals C and G have identical planar structure (Fig. 4).

Fig. (4))

Chemical structures of macrocarpals A-D and macrocarpal G.

Fig. (5))

Chemical structures of a few phloroglucinol glycosides (16-24).

Phloroglucinol Glycosides

From natural sources, some phloroglucinol O- as well as C-glycosides have been isolated. The phloroglucinol β-D-glucoside, phlorin (16), has been reported from Cannabis sativa [17]. Two structural equivalents of phlorin have been reported: picraquassioside D (17) from Artemisia annua and taxicatin (18) from Taxus baccata. Phloroglucinol O-glycosides with an acetyl functionality substituted at the ortho position on the aromatic ring include myrciaphenone A (19) and its galloyl derivative myrciaphenone B (20), reported from Myrcia multiflora [7].

Similarly, several phloroglucinol C-glycosides have been reported. Hydroxybenzoyl phloroglucinol-C-glycosides, including 3-glucosylmaclurin (21), was obtained from the leaves of Mangifera indica. Other equivalents include telephenones A and B (22 and 23) obtained from Polygala telephioides and 3-glucosyliriflophenone (24) reported from Hypodematium crenatum [7] Fig. (5).

Halogenated Phloroglucinols

Amongst marine organisms, a variety of halogenated phloroglucinols are known to occur. Vidalol A (25) and vidalol B (26) were isolated from Vidalia obtusaloba (Fig. 6) [18].

Fig. (6))

Chemical structures of a few halogenated phloroglucinols (25 and 26).

Prenylated/geranylated Phloroglucinols

Several geranylated and prenylated phloroglucinol compounds have been isolated. Acronylin (27) was reported from Acronychia pedunculata, such as prenylated phloroacetophenones [19] Fig. (7). Diprenylated acyl phloroglucinols as 4-deoxyadhumulone (28), deoxycohumulone (29) and 4-deoxyhumulone (30) were obtained from Humulus lupulus [20]. The prenylated hydroxybenzoyl phloroglucinols tovophenone A (31) and its cyclised equivalents tovophenone B (32) and tovophenone C (33) were reported from Tovomita brevistaminea [21]. Cudraphenone D (34) was isolated as another hydroxybenzoyl phloroglucinol with one prenyl functionality substituted on the aromatic ring from the roots of Cudrania cochinchinensis [22]. In Helichrysum species, a large number of prenylated acyl phloroglucinols are known to occur [23]. Caespitin (35) and caespitate (36) were isolated from H. caespititium [24].

Fig. (7))

Chemical structures of a few prenylated phloroglucinols (27-36).

Geranylated benzoyl phloroglucinols, such as pentacoccol (37) and 5-O-methylpentacoccol (38), comprising both geranyl and prenyl functionalities on the aromatic ring, were reported from Bosistoa pentacocca [25]. Some similar O-geranylated phloroglucinols have been isolated, among which the O-geranylphloroisobutyro-phenone, otogirin (39), which was isolated from Hypericum erectum (Fig. 8) [7].

Fig. (8))

Chemical structures of a few geranylated phloroglucinols (37-39).

Phloroglucinols Linked to a-pyrone Ring

Achyroclinopyrone (40) was isolated from Achyrocline alata as phloroglucinol α-pyrones with a geranyl functionality [26]. Italipyrone (41) and plicatipyrone (42) were reported from Helichrysum italicum and H. stoechas. Phloropyrones BB (43), PB (44) and BP (45) have been obtained from Ctenitis apiciflora and Ctenitis nidus [7] Fig. (9).

Fig. (9))

Chemical structures of a few phloroglucinols linked to α-pyrones (40-45).

Cyclic Polyketides

They are found in a number of plant species but largely in Eucalyptus. These differ in the level of oxygenation, the nature of the side chain and the number of methyl groups. The first member of this class of compounds, tasmanone (46), was soluble in sodium carbonate solution and gave other positive tests for acid [7].

Other polyprenylated phloroglucinols contain chinesins I (47) and II (48), reported from flowers of Hypericum chinense, and differ structurally from each other only in their acyl chain. Hyperatomarin (49), a structural equivalent of hyperpapuonone, has been obtained by bioassay-guided preparative TLC from H. atomarium ssp. Degenii [27] Fig. (10).

Miscellaneous Monomeric Phloroglucinols

Atrovirinone (50) is a phloroglucinic acid ester related to a quinone skeleton; it was reported from the roots of Garcinia atroviridis [28]. Ceanofendlin (51) was isolated from Ceanothus fendleri, it is a phloroglucinol linked to a tetrahydronaphthol [7].

Fig. (10))

Chemical structures of a few cyclic polyketides (46-49).

A phloroglucinol unit linked to a carboxybenzofuran ring, norwedelic acid (52) has been obtained from Wedelia calendulacea [29]. Moreover, compounds 2,4,6-trimethoxytoluene (53), 2,4,6-trimethoxystyrene (54) and pipermargin (55) have been isolated from Stockwellia spp., Zieria chevalieri and Piper marginatum, respectively, as other simple O- and C-alkylated compounds [30] Fig. (11).

Dimeric Phloroglucinols

This class contains compounds having two phloroglucinol units joined either through a methylene linkage or by the formation of a chroman ring. These compounds largely occur in the genera Aspidium (ferns), Dryopteris, Eucalyptus, Helichrysum, Hypericum, Mallotus and Myrtus and have also been found in some species of the genera Acronychia, Agrimonia, Euphorbia, Hagenia, Kunzea, and Melicope. They have also been isolated from microorganisms.

Fig. (11))

Chemical structures of a few monomeric phloroglucinols (50-55).

Dimers Formed by a Methylene Linkage

Bis (2,4-diacetylphloroglucyl)-methane (56) is the first member of this class and was obtained from the culture fluid of Pseudomonas aurantiaca. Later, robustaol A (57) was reported from leaves of E. robusta Smith. Further dimeric phloroglucinols isolated from the Myrtaceae family include semimyrtucommulone (58), reported from leaves of Myrtus communis [31]. Among dimeric phloroglucinol compounds which have been isolated from Hypericum spp, we have sarothralens B (japonicine B, 59), C (60) and D (61), sarothralens A (62) and G (63), reported from H. japonicum [32] Fig. (12).

Fig. (12))

Chemical structures of a few dimeric phloroglucinols formed by a methylene linkage (56-63).

Drummondins A–D (64–67) and those with prenyl side chains, drummondins E and F (68 and 69), have been reported from H. drummondii as dimeric phloroglucinols with a benzopyran ring skeleton [33] Fig. (13).

Fig. (13))

Chemical structures of a few dimeric phloroglucinols with benzopyran ring skeleton and prenyl side chains (64-69).

Fig. (14))

Chemical structures of some dimeric phloroglucinols isolated from Mallotus (70-84).

Dimeric phloroglucinols are also reported largely in Mallotus species. Mallotojaponin (70) and its numerous equivalents, butyryl mallotojaponin (71), isobutyryl mallotojaponin (72), mallotolerin (73), butyryl mallotolerin (74), isomalloto-chromene (75), butyrylmallatochromanol (76), isobutyryl mallotochromanol (77), malloto-chromanol (78), isomallatochromanol (79), mallotojaponol (80), iso-mallotolerin (81), prenylated compounds mallotochromene (82), butyrylmallatochromene (83) and isobutyrylmallatochromene (84) were isolated from Mallotus japonicus [11] Fig. (14).

Mallotojaponins B (85) and C (86) were obtained from the inflorescence and leaves of Mallotus oppositifolius [34]. In the leaves of the same plant, methylene-bis-aspidinol AB (87), methylene-bis-aspidinol, (88) mallopposinol (89), aspidinol B (90), acronyculatins S-U (91–93) and mallotojaponin D (94) were isolated as acylphloroglucinol derivatives [35, 36] Fig. (15).

Fig. (15))

Chemical structures of some phloroglucinols isolated from Mallotus oppositifolius (85-94).

Dimers Containing a Chroman Ring

Among dimeric phloroglucinol compounds with a chroman ring, sideroxylonals A–C (95–97) have been isolated from the leaves and flower buds of some species of Eucalyptus [37]. Sideroxylonals have a large array of biological effects and differ from each other in stereochemistry at C-7, C-7ꞌ and C-10ꞌ.

Grandinal (98) has been obtained from E. grandis and is similar to sideroxylonals, except that an isovaleryl group replaces one formyl group [38] Fig. (16).

Fig. (16))

Chemical structures of some dimers containing a chroman ring (95-98).

Fig. (17))

Chemical structures of some trimeric phloroglucinols (99-106).

Trimeric Phloroglucinols

Agrimols A–G (99–105) have been reported from Agrimonia pilosa and myrtucommulone A (106) from Myrtus communis as trimeric phloroglucinols [7, 39, 40] Fig. (17).

Tetrameric and Higher Phloroglucinols

Tetrameric and higher phloroglucinols are a type of phloroglucinol derivatives where a methylene linkage connects more than three phloroglucinol units. These phloroglucinol compounds contain tetraalbaspidin ABBA (107), isolated from Dryopteris crassirhizoma and tetraalbaspidin BBBB (108) reported from D. aitoniana and D. austriaca. From D. aitoniana, pentaalbaspidin BBBBB (109) and hexaalbaspidin BBBBBB (110) were also isolated as tetrameric phloroglucinol formed from flavaspidic acid and as hexameric phloroglucinol compound formed by the joining of albaspidin BB units [7] Fig. (18).

Fig. (18))

Chemical structures of few tetrameric and higher phloroglucinols (107-110).

Phlorotannins

They are generally polyphenolic compounds and are formed by polymerization of phloroglucinol units. A diversity of phloroglucinol-based polyphenols of high, intermediate and low molecular weight containing both phenyl and phenoxy units are in large amounts amongst marine organisms, especially brown and red algae, where they have been accumulated [7].

PLANT KINGDOM OF PHLOROGLUCINOLS COMPOUNDS AND THEIR USES

Beside the extensive interest in medicine, phloroglucinols are also used in cement, cosmetics, insecticides, paints, papers, pesticides and textiles, which are not included in the present chapter [8]. Phloroglucinol compounds are found in many families of the plant kingdom. Among these families, the most represented are Asteraceae, Euphorbiaceae, Hypericaceae, Lamiaceae, Myrtaceae and Rosaceae.

Asteraceae

Helichrysum caespititium and Helichrysum paronychioides are plants of the Asteraceae family. H. caespititium is a well-known perennial creeping herb and a valuable medicinal plant in Central and South Africa [41]. H. paronychioides is an indigenous plant mainly found in Botswana [42].

Both plants are broadly used as herbal medicines for many human diseases, as summarized in Table 1.

Table 1 Medicinal uses of H. caespititium and H. paronychioides.

Euphorbiaceae

Euphorbia ebracteolata, Mallotus oppositifolius and Mallotus phillipensis are plants belonging to the Euphorbiaceae family.

E. ebracteolata is a perennial herbaceous plant sporadically distributed in China, Korea and Japan [47]. M. oppositifolius is a plant species in the genus Mallotus found in secondary forests of Africa and Madagascar, and in savanna [35]. M. phillipensis is also a plant of the genus Mallotus, which has a large geographical array extending from North America and East Asia to Northern Indo-Pak [48].

The barks, fruits, leaves, roots and whole of these medicinal plants are used in traditional medicine for many diseases, as mentioned in Table 2.

Table 2 Medicinal uses of E. ebracteolata, M. oppositifolius and M. phillipensis

Hypericaceae

Many species belonging to the Hypericaceae family, particularly the Hypericum genus, have been studied due to the presence of phloroglucinols among their components. Among these species we have Hypericum ascyron, Hypericum Brasiliense, and Hypericum empetrifolium.

H. ascyron is a Chinese natural drug, which is a tall herbaceous perennial wildflower that usually grows in alluvial soils within floodplain habitats [49]. H. brasiliense is an annual bush native from Southern and Southeastern Brazil [50]. H. empetrifolium is a medicinal plant found throughout the coastal area of western Turkey and the southern part of the Grecian mainland [51].

The different parts of these three species are used to treat diseases, as mentioned in Table 3.

Table 3 Medicinal uses of H. ascyron, H. Brasiliense, and H. empetrifolium

Lamiaceae

Helichrysum italicum is a flowering plant from the Mediterranean area. It is a well-known medicinal plant with a strong and persistent smell reminiscent of that of curry [31]. Pogostemon auricularius is an annual herb largely distributed in Bangladesh, China, India, Sri Lanka, and Southeast Asia [53]. Some of the parts of these two plants have been used to treat different diseases in traditional folk medicine, as mentioned in Table 4.

Table 4 Medicinal uses of H. italicum and P. auricularius

Myrtaceae

Many plants belonging to the Myrtaceae family and which contain phloroglucinol compounds have been studied for their uses. Among these species we have Eucalyptus globulus, Leptospermum scoparium, Rhodomyrtus tomentosa and Syncarpia glomulifera.

E. globulus, commonly known as blue gum, is autochthonous to Australia and is now broadly cultivated in Southern and Southwestern China, particularly in Jiangxi and Yunnan provinces [54]. L. scoparium is distributed largely in New Zealand; it is an upright evergreen shrub with aromatic, showy and small flowers [55]. R. tomentosa is an edible and medicinal plant and is broadly spread in some tropical and subtropical countries, such as Malaysia, Philippines, and Vietnam, and also in Southern China [56]. S. glomulifera, usually known as the turpentine tree, is a tree native to New South Wales and Queensland in Australia [57].

The barks, fruits, leaves, roots and whole of these plants have been used by populations to treat different diseases, as shown in Table 5.

Table 5 Medicinal uses of E. globulus, L. scoparium, R. tomentosa and S. glomulifera

Rosaceae

Agrimonia Pilosa is a medicinal plant distributed in China, Japan, Korean Peninsula, Siberia and Eastern Europe [58] Table 6.

Table 6 Medicinal uses of A. Pilosa

PHARMACOLOGICAL ACTIVITIES OF PHLOROGLUCINOL COMPOUNDS

Phloroglucinols are polyphenolic compounds whose chemical structure contains an aromatic phenyl ring with three hydroxyls. Phloroglucinols have shown a large array of biological activities such as antibacterial, antifungal, anti-inflammatory, antileshmanial, antiplasmodial, cytotoxic, ferroptosis, etc. The reported pharmacological activities of phloroglucinol compounds are detailed below.

Antibacterial Activity

A study showed that six compounds 85, 86, 91–94 isolated from Mallotus oppositifolius were tested for their antibacterial activities against six bacterial strains representing human pathogens, which are five gram-negative isolates, Escherichia coli ATCC 25922, Klebsiella pneumonia ATCC 700603, Pseudomonas aeroginosa HM 601, Salmonella typhi, and Shigella flexneri NR 518 and one gram-positive Staphylococcus aureus ATCC 43300. The results showed that these compounds exhibited variable antibacterial activities, with mallotojaponin B (85) being the most active (3.125 μg/mL), while mallotojaponin C (86) and mallotojaponin D (94) were moderately active against specific microorganisms. These compounds also showed significant activities against the diarrheal-manifesting E. coli and P. aeruginosa as well as typhoid-causing S. typhi and food-poisoning S. aureus. Any of them was active against S. flexneri and K. pneumonia [36].

Antifungal Activity

Six fungi, Aspergillus flavus, Aspergillus niger, Cladosporium cladosporioides, Cladosporium cucumerinum, Cladosporium sphaerospermum and Phytophthora capsica, were tested in order to evaluate the antifungal activity of 2-methyl-4-[2',4',6'-trihydroxy-3'-(2-methyl-propanoyl)-phenyl]but-2-enyl acetate (111), which is acylated phloroglucinol, reported from Helichrysum caespititium [24] Fig. (19).

Fig. (19))

Chemical structure of an acylated phloroglucinol isolated from H. caespititium.

These fungi were inhibited at low minimum inhibitory concentrations with A. flavus and A. niger at 1.0 µg/mL, C. cladosporioides at 5 µg/mL, C. cucumerinum and C. sphaerospermum at 0.5 µg/mL and P. capsici at 1.0 µg/mL [18].

Anti-inflammatory Activity

Two acylphloroglucinol derivatives 112 and 113 isolated from Hypericum empetrifolium for their potent In vitro anti-inflammatory activity were assessed for In vitro inhibitory activity against cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase catalyzed leukotriene B4 formation. Compound 112 exhibited good activity (IC50 values: 6.0, 29.9, and 2.2 µM, respectively) in all three assays. Compound 113 displayed good activity (IC50 value: 5.8 µM) against leukotriene B4 formation and moderate activity (IC50 value: 26.2 µM) against cyclooxygenase-1 [51] Fig. (20).

The anti-inflammatory activity of the isolated compounds 114–121 was evaluated according to the inhibitory effects on LPS-induced NO production in RAW 264.7 [56] Fig. (21).

Fig. (20))

Chemical structures of two acylphloroglucinol derivatives isolated from H. empetrifolium (112 and 113).

Fig. (21))

Chemical structures of a few acylphloroglucinol derivatives isolated from Rhodomyrtus tomentosa (114-121).

In comparison with the IC50 of the positive control (indometacin), which was 126.25 ± 1.26 μM, the results showed that all these compounds exhibited better potential anti-inflammatory activities with IC50 of 3.80 ± 0.43 to 74.30 ± 1.26 μM. These values suggest that compounds isolated from Rhodomyrtus tomentosa can play a significant role in the anti-inflammatory activity [56].

Antileishmanial Activity

The activity of compounds 87-90 was assessed for the antiprotozoal properties of compounds against Leishmania donovani promastigotes and Trypanosoma brucei trypomastigotes. The compounds, methylene-bis-aspidinol AB (88) and aspidinol B (90), displayed moderate antileishmanial activity with EC50 of 21.3 and 38.8 μM, respectively. These results also showed that the reference drug sitamaquine (EC50 35.4 μM) is less active than the compound 88 (EC50 21.3 μM). On Trypanosoma brucei, the trypanocidal activity of the reference drug pentamidine (LC100 0.4 μM) was similar to methylene bis-aspidinol (LC100 =0.8 μM) [35].

Antiplasmodial Activity

A study showed that compounds 122–123 exhibited strong to weak inhibition of the growth of the strain of P. falciparum, with Rhodomyrtosone (122) displaying the strongest activity with an IC50 of 0.10 ± 0.02 µM. Rhodomyrtosone thus seems to be a potent and relatively non-toxic antimalarial agent. Calliviminone (123) displayed moderate antiplasmodial activity (IC50 3.81 ± 1.14 µM) and showed in its structure the spiro- [5, 5]-undec-8-ene skeleton, which is an isolated phloroglucinol compound with antiplasmodial activity [59] Fig. (22).

Fig. (22))

Chemical structures of two phloroglucinol derivatives with antiplasmodial activity (122 and 123).

Another evaluation of the activity of mallotojaponin B (85) and mallotojaponin C (86) against Plasmodium falciparum Dd2 (a chloroquine/mefloquine-resistant strain) displayed submicromolar activity (IC50 0.75 ± 0.30 and 0.14 ± 0.04 μM respectively) and also exhibited cytocidal activity vs P. falciparum. Regarding the determination of cytocidal activity, chloroquine displayed (LD50 0.10 ± 0.01 μM) vs (LD50 15.3 ± 0.9 μM) of the drug-sensitive HB3 strain and the drug-resistant Dd2 strain, respectively. In these same assays, mallotojaponin B was found to have (LD50 14.6 ± 0.7 and 6.7 ± 0.2 μM, HB3 vs Dd2) while mallotojaponin C had (LD50 0.81 ± 0.05 and 0.80 ± 0.02 μM) vs the same two strains. The results showed that mallotojaponin C is significantly more cytocidally potent than chloroquine [34].

Antiproliferative Activity

The antiproliferative activity of some phloroglucinols isolated from Hypericum Brasiliense was evaluated. In this regard, japonicin A (124), uliginosin B (125) and isouliginosin B (126) were assessed against the proliferation of tumor cells, such as breast (MCF-7), colon (HT-29), melanoma (UACC-62), ovarian (OVCAR-03) and prostate (PC-3) [50] Fig. (23).

Fig. (23))

Chemical structures of some phloroglucinols isolated from H. Brasiliense (124-126).

Among these substances, uliginosin B was the most active (mean TGI = 3.91 μg/mL) derivative phloroglucinol, while isouliginosin B presented a weak antiproliferative activity (mean TGI =21.03 μg/mL) and japonicin A was inactive (mean TGI = 148.44 μg/mL). These results exhibited that the increase of antiproliferative activity is related to the isoprenyl unit in phloroglucinol derivatives [50].

Cytotoxicity Activity

Tomoeones A–H (127-134) were evaluated for their cytotoxicity against human tumor cell lines, including multidrug-resistant (MDR) cancer cell lines (KB-C2 and K562/Adr). The cytotoxicity of tomeone A (127) and tomeone B (128) showed IC50 values ranging from 17.1 to 48.0 µM, while the cytotoxicity of tomeone F (132) against MDR cancer cell lines was more toxic than doxorubicin: IC50 >100 µg/mL (KB-C2); 28.1 µM (K562/Adr) [49]. Tomeone A (127) and tomeone B (128) also displayed potent cytotoxicity against KB cells with IC50 values of 6.2 and 17.1 µM, respectively Fig. (24).

Fig. (24))

Chemical structures of tomeones A–H (127-134).

Fig. (25))

Chemical structures of a few phloroglucinol derivatives with cytotoxicity activity (135-139).

In general, compounds with a 2-methylpropanoyl group at C-2 were less toxic than compounds having a 3-methylbutanoyl group at C-2. Furthermore, compounds 129, 130, 133, and 134 were less cytotoxic than 127, 128, 131, and 132, in which all the former compounds had the axial CH3 at C-13, and then, the configuration of CH3-15 can enhance their cytotoxicity too [49].

In another study, an MTT assay was used to evaluate the cytotoxicity activity of compounds 135-139 against A-549, MDA-MB-231, HCT-116 and PC-3 cancer cell lines, and the positive control used was the anti-cancer drug fluorouracil. The results showed that the five compounds displayed more potent inhibitory activities against all the cancer cell lines than the positive control fluorouracil except A-549. Significant cytotoxicity on colonic cancer cells HCT-116 was exhibited by these compounds [60]. This result exhibited that the dimeric phloroglucinol nucleus was a key group for the retention of their activities [61]. However, arzanol, a phloroglucinol α-pyrone, had non-significant cytotoxicity [62]. The two symmetric