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Anthraquinones as potential antimicrobial agents-A review
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Anthraquinones as potential antimicrobial agents - A review
M. Malmir, R. Serrano and O. Silva*
Research Institute for Medicines ([Link]), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama
Pinto, 1649-003 Lisbon, Portugal
Ethnopharmacological studies on antimicrobial traditional herbal preparations have gained much attention in recent years.
In fact, in the last 30 years, 2/3 of the new antibacterial drugs were of natural source and among them, plants were mainly
used. In addition, the emergence of new drugs active against resistant strains (e.g. the ESKAPE pathogens) to the actual
chemotherapy, reinforces the interest of the prosecution of the studies concerning the discovery of new antibiotics from
natural sources. Anthraquinones and their derivatives are a class of aromatic compounds with a 9,10-dioxoanthracene core.
Considering the great structural diversity and variations in chemical composition, numerous antimicrobial in vitro and/or
in vivo activities of natural and synthetic anthraquinones have been reported, however there has been limited research
related to the structural-functional relationship of these compounds. The present study aimed to provide a comprehensive
review of the available literature on chemical structure, mechanism of action and safety of anthraquinones as promising
sources of antimicrobial lead-compounds.
Keywords: Anthraquinone derivatives; antimicrobial activity; emodin; natural sources
1. Introduction
Antimicrobial resistance (AMR) is a growing global healthcare problem due to the loss of efficacy of first line
antibiotics. Many pathogens are developing resistance to multiple drugs, some to nearly all [1]. The major resistance
overall issues being related to the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), specially to methicillin-
resistant Staphylococcus aureus (MRSA), extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae,
fluoroquinolone-resistant (FQR) Gram-negative bacteria, multidrug-resistant (MDR) Pseudomonas aeruginosa, and the
emerging vancomycin-resistant enterococci (VRE) [2].
The emergence of these new pathogens caused worldwide agencies to unite efforts in the discovery and development
(D&D) of new antimicrobial drugs [3-4].
The first step of drug D&D is lead discovery, for which academia has made important contributions in the past (e.g.
penicillin, streptomycin). Only a small fraction of marine, fungal and plant resources have been chemically and
pharmacologically investigated, although nature still offers a high potential for drug lead discovery notably among anti-
infective compounds [5]. In fact, in the last 30 years, 2/3 of the new antibacterial drugs were of natural source and
among them, plants were mainly used [6].
Several plant-derived chemical compounds have been studied with this aim, including alkaloids, flavonoids, tannins,
quinones, volatile terpenoids and phenol acids and other secondary metabolites. Among them, anthraquinone
derivatives (AQ) have aroused special interest since they have demonstrated potential therapeutic uses as antibacterial,
antiviral, antifungal as well as antioxidant, anti-inflammatory and cytotoxic agents[7]. Both natural and synthetic
anthraquinones have now widespread application throughout industry and medicine. Important anthraquinone-bearing
plant families are the Caesalpiniaceae, Polygonaceae, Rhamnaceae and Rubiaceae, and this class of compounds became
marker chemical classes with chemotaxonomic significance to these plant families [8].
Anthraquinones and their derivatives are a class of aromatic compounds with a 9,10-dioxoanthracene. Although they
exhibit great structural diversity and variations in chemical composition, they are divided into two main types: alizarin
and emodin. The alizarin type is used as natural dye in the textile industry, while the emodin type was formerly used as
laxative agent.
The in vitro antimicrobial activity of the emodin type anthraquinone compounds have been reported in many
different studies [9]. The chemical structures of the main antimicrobial anthraquinones of this type are shown in Fig.1.
For instance:
- Aloe-emodin, a typical Aloe species anthraquinone was showed to inhibit Herpes simplex viruses (HSV-1, HSV-
2), varicella-zoster virus, pseudorabies virus, influenza virus, MRSA, Aspergillus fumigatus, Bacillus subtilis
Candida albicans, Cryptococcus neoformans, Helicobacter pylori and Trichophyton mentagrophytes;
- chrysophanol, a constituent of Rheum species, inhibited A. fumigatus, C. albicans, C. neoformans, T.
mentagrophytes, Poliovirus type 2 and type 3;
- 8–dihydroxyanthraquinone, a marker compound of Senna occidentalis, inhibited Clostridium perfringens and
Staphylococcus aureus;
- Emodin, found in several species and particularly in Rhamnus frangula, inhibited MRSA, cytomegalovirus
(CMV), HSV-1, HSV-2, B. subtilis, Helicobacter pylori, Heterobasidion annosum, Leishmania donovani,
Plasmodium falciparum and Trypanosoma spp.;
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- Hypericin, an anthraquinone derivative found in Hypericum perforatum, inhibited HSV-1 and HSV-2, human
immunodeficiency virus, human papillomavirus (HPV-1, HPV-6, HPV-11, HPV-16, and HPV-18), methicillin sensitive
Staphylococcus (MSSA), MRSA, H. pylori, B. subtilis and Bacillus cereus;
- Physcion, also a typical constituent of Rheum species inhibited HSV-1 and HSV-2, CMV, C. albicans, C.
neoformans, T. mentagrophytes, and Aspergillus fumigatus;
- Rhein inhibited A. fumigatus, Bacteroides fragilis, B. subtilis, C. albicans, C. neoformans, H. pylori, MRSA,
Neisseria gonorrhoeae and Streptococcus viridans and T. mentagrophytes [10].
Hereby a brief update about anthraquinones antimicrobial activity, given an overview on their mechanism of action
and their structural-functional studies will be presented.
Fig. 1 Principal emodin type anthraquinone natural products
2. Reported antimicrobial activities of anthraquinones
The antimicrobial activities of anthraquinones have been extensively studied in vitro on pure compounds or in crude
plant extracts containing these class of constituents as marker compounds. Most of them exhibit positive activity against
a large panel of reference of the most common pathogens, including the main causative agents of currently no treatable
infections. Details of representative studies will be presented in this section.
The methanolic extract of the root of Colubrina greggii showed antimicrobial activity against B. subtilis and S.
aureus. The bioassay-guided purification of the organic crude extract resulted in the isolation and identification of
chrysophanol (1,8-dihydroxy-3-methylanthracenedione), as the metabolite responsible for the antimicrobial activity of
the extract [11].
The minimum inhibitory concentration (MIC) value of Aloe vera gel and Aloe vera juice were evaluated against
Bacillus subtilis ATCC6633, Escherichia coli ATCC10418, Enterococcus faecalis ATCC29212, Salmonella
typhimurium ATCC29922, Staphylococcus aureus ATCC6571, Staphylococcus epidermididis ATCC29213, Proteus
vulgaris ATCC13315 and Pseudomonas aeruginosa ATCC1062. Aloe vera juice showed an inhibitory effect against all
the microorganisms but Aloe vera gel was only effective against S. aureus (10.54± 0.43 mm). In sequence, MIC was
determined for the Aloe vera juice having it shown to be especially active against Proteus vulgaris. It could be theorized
that presence of greater amount of the anthraquinones in the extract could be responsible for the high and broad
spectrum antimicrobial activity of the juice as compared to gel [12], although Aloe vera inner gel (containg emodin,
aloe-emodin, chrysophanol, rhein and physcion) expressed antibacterial properties against both susceptible and resistant
Helicobacter pylori strains (MIC: 6.25-400 μg/mL). which may impact on the antimicrobial resistance phenomenon of
H. pylori, proposing the A. vera inner gel as a novel effective natural agent in combination with antibiotics for the
treatment of H. pylori gastric infection [13].
Antibacterial activity of a crude extract from Rheum rhabarbarum and its major bioactive compounds (aloe-emodin,
rhein, emodin, chrysophanol, and physcion) was evaluated against Aeromonas hydrophila (Gram-negative, rod-shaped
bacterium). The antibacterial activity given by MIC was positively related to the anthraquinone content (r = 0.9306,
P<0.01) and the MIC values of the five isolated anthraquinones against A. hydrophila were found to be in the range 50–
200 µg/mL [14].
In another study regarding several species of the same genus, the crude ethanol extracts obtained from the rhizome
and roots of Rheum palmatum, Rheum undulatum and Rheum rhaponticum. showed a higher activity against reference
strains of Gram-positive bacteria (Staphylococcus spp.) than against Gram-negative bacteria (Escherichia coli,
Klebsiella pneumoniae and Proteus mirabilis). The strongest inhibitory effect against Staphylococcus spp. was exerted
by R. undulatum extract (MIC = 125-250 μg/mL) and it was found that the active constituents were anthraquinones
derivatives, including aloe-emodin, emodin and rhein. The moderate in vitro antibacterial activity of R. undulatum
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suggested that this plant could be used in the treatment of uncomplicated superficial infections caused by clinically
important staphylococci, potentially pathogenic S. aureus or opportunistic S. epidermidis [15].
More interestingly, the antimicrobial activity of emodin isolated from Rheum palmatum was examined against 15
clinical isolates of MRSA. The results showed the MICs of emodine against S. aureus ranged from 1.56–25 μg/mL.
This compoundvmarkedly lowered the MICs of amoxicillin and oxacillin tested against the same MRSA strains,
resulting in a synergetic effect between this marker compound and these antibiotics [16].
Anthraquinones were detected in ethanol extracts along with acetone and ethyl acetate fractions of both fruits fibers
and fruits cover of Adansonia digitata (baobab tree). Fruit covers extract exerted highest activity on tested bacterial
agents (B. subtilis, P. vulgaris, S. aureus). In comparison to fruits fibers extract, fruits cover extract was more effective
against fungi (Aspergillus niger), while both extracts did not show activity against C. albicans [17].
A bio-guided fractionation study was performed to evaluate the antibacterial activity of Senna podocarpa root hydro-
ethanol extract against nine Neisseria gonorrhoeae reference and clinical strains, some with diminished susceptibility to
penicillin, tetracycline, and ciprofloxacin. The results showed the anti-N. gonorrhoeae activity against all tested strains,
with a MIC ranging from 100 to 400 μg/mL. Rhein, emodin, chrysophanol and physcione were isolated as main
compounds and rhein (MIC = 3.13 μg/mL against all test strains) proved to be the most active of the isolates [18].
Emodin isolated from several Cassia species showed activity against B. subtilis ( MIC = 7.8 μg/mL) and S. aureus
(MIC = 3.9 μg/mL) but was inactive against two Gram-negative bacteria (K. pneumoniae and E. coli) at the highest
concentration (500 μg/mL) tested [19]. It showed also weak activity against S. pyogenes and S. typhi (MIC = 3000
μg/mL) as well as N. gonorrhoea and C. albicans MIC = 4×103 μg/mL [20]. In another study it was indicated that, the
antimicrobial effect of emodin against MRSA strains was higher than many antibiotics including imipenem, cefepime
[21] or chloramphenicol [22]. Antimicrobial resistance can be defined as more than a fourfold increase in original MIC
of antibiotic. In this case, there was no MIC increase for emodin during 20 passages, which suggested that MRSA did
not develop resistance for emodin. For norvancomycin, MIC got a twofold increase at passage 4 and a fourfold increase
at passage 15 which demonstrated the emergence of resistance. These results suggested it was not easy for emodin to
cause MRSA resistance [21].
Antimicrobial activity of several anthraquinone derivatives such as 1,8-dihydroxy-2-[(z)-4-methylpenta-1,3-dien-1-
yl] anthraquinone, 2-acetyl-3,8-dihydroxy-6-methoxyanthraquinone, emodin and glucofrangulin A, isolated from the
methanolic extract of Rhamnus cathartica showed that 1,8-dihydroxy-2-[(z)-4-methylpenta-1,3-dien-1-yl]
anthraquinone and emodin exhibited activity against E. coli and S. aureus and anti-yeast activity against C. albicans.
The 2-acetyl-3,8-dihydroxy-6-methoxyanthraquinone only exhibited activity against E. coli. All compounds together
with the methanol extract showed negative effect against A. niger [23]. On the other hand aloe-emodin was capable of
inhibiting the growth of both Gram-positive and Gram-negative bacteria as well as inhibiting the growth of a nystatin
resistant strain of the fungus A. niger [24].
Antimicrobial results obtained from the isolated compounds of Tabebuia impetiginosa dried inner bark showed that
2-(hydroxymethyl)anthraquinone exhibited strong activity against H. pylori ATCC43504 at 0.01 mg/disc.
Anthraquinone-2-carboxylicacid and metronidazole were less effective, exhibiting moderate anti-Helicobacter pylori
activity at 0.1 mg/disc. Amoxicillin and tetracycline were the most potent compounds tested, displaying very strong
activity at 0.005 mg/disc. 2- (hydroxymethyl) anthraquinone exhibited moderate activity at this dose. Tetracycline still
had strong activity at 0.001 mg/disc while amoxicillin had little activity at this dose [25].
The 8-methoxychrysophanol and other isolated compounds from Asphodelus microcarpus exhibited moderate
antifungal activity against C. neoformans with an IC50 value of 15.0 μg/mL, while emodin, 10-(chrysophanol-7′-yl)-10-
hydroxychrysophanol-9-anthrone and aestivin showed good to potent activity against MRSA with IC50 values of 6.6,
9.4 μg/mL and1.4 μg/mL respectively. Emodin and ramosin displayed good activity against S. aureus with IC50 values
of 3.2 and 8.5 μg/mL [26].
The soranjidiol, rubiadin, damnacanthal and 5,5’-bisoranjidiol isolated from Heterophyllaea pustulata showed
antibacterial activity against S. aureus with MICs between 32 µg/mL to 64 µg/mL [27].
An hexanic crude extract from leaves and roots of Ceratotheca triloba and its anthraquinones derivatives were also
studied. Isolated compounds, 9,10-anthracenedione and 1-hydroxy-4-methylanthraquinone showed antibacterial activity
against S. aureus, Micrococcus luteus, B. cereus and Escherichia coli. The crude extract exhibited good activity against
S. aureus and M. luteus, medium activity against E. coli and S. typhimurium and very low activity against B. cereus.
Although a similar trend was observed for 9,10 anthracenedione and 1-hydroxy-4-methyl anthraquinone, unlike the
crude extract, a very low activity against S. aureus was observed for 9,10 anthracenedione and a high activity for 1-
hydroxy-4-methylanthraquinone. Thus 9,10 anthracenedione is an effective drug against E. coli and S. typhimurium and
1-hydroxy-4-methylanthraquinone is effective against S. aureus and M. luteus [28].
The methyl-1,4,5-trihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate, also isolated from
Asphodelus microcarpus showed a potent activity against MRSA and S. aureus with IC50 values of 1.5 and 1.2 µg/mL
respectively [29]. Compounds identified as asphodosides B, C and D showed activity against MRSA with IC50 values of
1.62, 7.0 and 9.0 µg/mL, respectively. They also exhibited activity against S. aureus (non-MRSA) with IC50 values of
1.0, 3.4 and 2.2 µg/mL, respectively [30].
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3. Reported mechanisms of actions of anthraquinones
Several mechanisms of actions of anthraquinones (as pure compounds or as marker compounds of crude extracts) were
reported from different studies. In some cases, the indicated mechanisms were different from those of most common
antimicrobial agents as it will be stated later in this section. As already stated the chemical structures of the main
antimicrobial anthraquinones of this study are shown in Fig.1.
3.1 Action-mode studies
3.1.1 Cell wall synthesis and membrane function inhibition
Emodin, dose-dependently protected mice challenged with lethal dose of MRSA and decreased bacterial load in mice
challenged with sublethal dose of MRSA. Morphology observation showed emodin might disrupt cell wall and
membrane of MRSA. Although emodin had no influence on genes related to cell wall synthesis and lysis as well as β-
lactamase activity and drug accumulation, it reduced membrane fluidity and disrupted membrane integrity [21].
Extracts of Curtisia dentata demonstrated high antimicrobial activity and low minimum inhibitory concentrations
against E. coli (MIC, 100–2500 µg/mL), Acinetobacter haemolyticus (MIC, 100–850 µg/mL) and Acinetobacter lwoffii
(MIC 150–2500 µg/mL), by inducing the leakage of Na+ and K+ from the tested bacteria as well as an inhibitory action
against the expression of both Vtx1 and Vtx2 genes, responsible for the production of verocitotoxins [7].
3.1.2 Nucleic acid synthesis inhibition
In one study it was concluded that one of the antibacterial mechanisms of emodin was its ability to bind with the
phosphate group of DNA and intercalate into the base pairs of the DNA helix. In this way it would affect replication
and transcription, repress expression and even lead to cell death [14].
It has been demonstrated that anthraquinones extracted from different species of Aloe exhibit antibacterial activity by
inhibition of nucleic acids synthesis in [Link] [31].
3.1.3 Other metabolic processes inhibition
Antimicrobial activity of 1,8- dihydroxyanthraquinones (DAD) is related to their inhibition activity on the enzymes
which are necessary to microorganisms. Penicillase is inhibited by rhein, emodin and aloe-emodin. HIV-1 reverse-
transcriptase is inhibited by hypericin. The activity of N-acetyltransferase in H. pylori decreases with increasing levels
of rhein and the 1,8- DAD also exhibit antibacterial activity by inhibiting nucleic acid synthesis [10].
Emodin has shown a general antimicrobial effect against several microorganisms because of its capacity to interfere
with cellular metabolism. It can cause inhibition of electron flow in the respiratory chain, most likely in between
ubiquinone and cytochrome b, and also cause dissipation of the proton motive force [32], which may explain in part the
anti-staphylococcal activity of Rheum palmatum extract. In one study, emodin showed minimal antibacterial activity
against some Gram-negative MDR strains including E. coli, and K. pneumoniae, however, there was substantial
enhancement of its activity with PaβN (efflux pump inhibitor) [22].
It was showed that anthraquinone-rich extracts, obtained from the phototoxic Heterophyllaea pustulata (Rubiaceae),
exhibited bacteriostatic activity against M. luteus ATCC 9341, selectively inhibiting both oxacillin-sensitive and
resistant S. aureus, and antifungal activity against important opportunist microorganisms and against those involved in
superficial mycosis, all from nosocomial origin. In this context, soranjidiol, rubiadin, damnacanthal and (S)-5,5'-
bisoranjidiol, showed in vitro bacteriostatic/bactericide activity against S. aureus. The mechanism of action seems to
involve an increase in the levels of superoxide anion and/or singlet oxygen molecular.
The 5,5'-bisoranjidiol showed higher antibacterial activity than rubiadin and soranjidiol, although the three increase
O2.- production at about the same level as a function of regardless that they are acting in darkness or under irradiation. In
contrast, the 1O2 production for 5,5'-bisoranjidiol was high irrespective of conditions (darkness or irradiation). This
would suggest that, among the different species that comprise ROS (radical oxygen species), 1O2 is the one mainly
involved in the bactericidal effect. This increase in ROS could result from the interaction between bacteria and the
anthraquinones without needing light [33], although, actinic irradiation generated a photosensitization for rubiadin,
soranjidiol and 5,5'-bisoranjidiol, which consequently increased their antibacterial effects (particularly, bactericide)
[27]. It’s noteworthy that the bactericidal effect is suppressed when a specific quencher of 1O2 is added, thus suggesting
that the bactericidal activity derives mainly from that particular ROS [33].
Anthaquinones do not have simply antibactericidal effect but they are also able to decrease the pathogenicity of
certain bacteria. Alizarin at 10 μg/mL was found to efficiently inhibit biofilm formation by three S. aureus strains and a
S. epidermidis strain. Binding of Ca2+ by alizarin decreased S. aureus biofilm formation and a calcium specific chelating
agent suppressed the effect of calcium. In addition, two other anthraquinones, purpurin and quinalizarin, were found to
have antibiofilm activity. These three anthraquinones also markedly inhibited the hemolytic activity of S. aureus, and
in-line with their antibiofilm activities, increased cell aggregation. Transcriptional analyses showed that alizarin
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repressed the α-hemolysin hla gene, biofilm-related genes (psmα, rbf, and spa), and modulated the expressions of
cid/lrg genes (the holin/antiholin system). These findings suggest anthraquinones, especially alizarin, are potentially
useful for controlling biofilm formation and the virulence of S. aureus [34].
Some studies revealed that rhein has the ability to attenuate the virulence of Porphyromonas gingivalis by
significantly reducing the expression of genes coding for important virulent factors, which are involved in bacterial
adhesion, host defence mechanisms, tissue destruction, and nutrient acquisition [35], also rhein differentially regulated
the expression of genes involved in bacterial physiology and pathogenicity of S. aureus [36-37]. These studies revealed
the great potential for synergetic antibacterial activity between rhein and other class of antibiotics which might help to
solve the problem of antibacterial resistance, once that pathogens are not exposed to these phytochemical compounds
and therefore unlikely to develop resistances [35].
The combination effect of emodin with amoxicillin and oxacillin was found to be synergistic or partially synergistic.
It was found that emodin reduced MICs of amoxicillin, tetracycline and oxacillin [16, 38] and showed antibacterial
activity against H. pylori MDR possibly via mechanisms associated with altering hefA gene expression associated with
efflux pump mechanism [38].
3.2 Structural-functional studies
In general, the anti-bacterial effects of emodin, rhein, and aloe-emodin are generally higher than those of physcion and
chrysophanol. These anthraquinone derivatives have the same hydroxyanthraquinone nucleus composed of two ketone
groups at C9 and C10 and two hydroxyl groups at C1 and C8, while different groups are substituted at C3 and C6 of the
phenyl ring. Three anthraquinones (rhein, emodin, and aloe-emodin) have polar substituents - carboxyl, hydroxyl, and
hydroxymethyl groups at C3, C6, and C3, respectively. It was reported that the presence of these polar functional
groups could increase antibacterial activity. Although physcion and chrysophanol also have hydroxyl groups at C1 and
C8, the apolar methyl and weakly polar methoxyl groups in chrysophanol and physcion might weaken their antibacterial
activity [14].
In one study, anthraquinones isolated from Vismia laurentii were tested against a panel including Gram positive (B.
cereus, Listeria monocytogenes and S. aureus) and Gram negative microorganisms (E. coli, C. albicans and Salmonella
enteritidis). According to the obtained results, 3- geranyloxyemodin was bactericidal to the three Gram positive bacteria
strains with activity increasing with pH while 3-methoxyemodin was active only on S. aureus with activity decreasing
with pH. On the other hand 2-isoprenyl-3-methoxyemodin was active only at pH7 and only on S. aureus and B. cereus
[9].
The antimicrobial activity of 1,8- dihydroxyanthraquinones (DAD) against some strains of bacteria depends upon
their chemical structures. Rhein, emodin and 1,8-dihydroxyanthraquinone in decreasing order, inhibit the growth of S.
aureus. However, the anti-bacterial activity of oxidized 1,8-DAD decreased when they changed to their reduced forms.
The 1,8 -DAD are phenolic compounds contain hydroxyl groups in various positions of the anthraquinone molecule, so
that they exhibit a various degree of antimicrobial activity, depending on the OH- group [10].
In another study it was found that presence of an hydroxyl group in place of a methyl group at C3 or a methyl in
place of hydroxyl group at C8 and an additional methyl ester (COOMe) group at C7 as in 3,6,8-trihydroxy-1-
methylanthraquinone-2-carboxylic acid substantially reduced antimicrobial activities especially against the MRSA
phenotype [22]. One more study that also stressed the importance of hydroxyl group position was the work on Morinda
angustifolia root extract, which resulted in the isolation of 1,8-dihydroxy-2-methyl-3,7-dimethoxyanthraquinone (1),
lucidin 3-O-β-primeveroside (2), 1,3-dihydroxy-2-methylanthraquinone (3), lucidin-ω-ethyl ether (4), lucidin-ω-butyl
ether (5) and damnacanthol (6). Compound 1 (1,8-dihydroxy-2-methyl-3,7-dimethoxyanthraquinone) demonstrated
significant higher antimicrobial activity against B. subtilis, E. coli, M. luteus, Sarcina lutea, C. albicans and
Saccharomyces sp. in comparing to the others tested. Interestingly, only this compound possesses an additional
hydroxyl group at C-8, which might suggest that the structural fragment with a carbonyl and two β-hydroxyls at a linear
position in anthraquinones might be an important pharmacophore for the antimicrobial bioactivities [39].
A study of chemical structure-activity relationship study revealed that two hydroxyl units at the C-1 and C-2
positions of alizarin play important roles in antibiofilm and anti-hemolytic activities [34]. Isolated anthraquinones from
roots dried powder of Vismia laurentii were classified in terms of decreasing antimicrobial activity such as 3-
geranyloxyemodin (A), 3-ethoxyemodin (C), 2-isoprenyl-3-methoxyemodin (D), vismiaquinone (B) and
bisvismiaquinone (E). It was assumed that steric effect, weight and the presence of substitutions in position 2 of emodin
derivatives is detrimental to their bactericidal activity while increase in the aliphatic chain length of the methoxy
substitution in position 6 is beneficial to the antibacterial activity of these emodin derived anthraquinones. Gram
positive bacteria and C. albicans cells have their cell walls exposed, and compounds that can interact with these cell
walls should have a long aliphatic chain to help disorder the cell wall. This was case of compound A compared to
compounds C and D. Substitution in position 2 of the emodin was detrimental for the antibacterial activity of these
compounds while the unsaturation of the substitute was noticed to be important for this activity. The increase of the
aliphatic chain length of the methoxy substitute in position 3 increased the lipophilicity of the compound. The
antimicrobial activity, which is increased by the lipophilicity of the compound, is reduced as the compound molecular
weight increases [9].
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4. Overall conclusion
Aloe-emodin, chrysophanol, emodin, physcion and rhein are the anthraquinones identified in nature with the highest
number of studies proving their in vitro antimicrobial activity, against a set of microorganisms sensitive and resistant to
antimicrobial drugs currently available for clinical use.
In general, extracts and isolated anthaquinones were active against Gram negative bacteria, particularly against
Pseudomonas aeruginosa, Helicobacter pylori and Neisseria gonorrhoeae and Gram positive bacteria such as
Staphylococcus aureus, namely MRSA strains and S. epidermitis. The synergic activity of anthraquinones with other
antibiotics, resulting in a smaller MIC was also proved.
The antibacterial mechanisms of anthraquinones are diverse, including the simple destabilization of cell wall,
alterations of metabolic pathways or DNA inclusions, in a direct or indirect way (via oxidative stress). The efficacy of
these mechanisms is related to the molecular properties of the anthraquinone (steric effect, pH, polarity of group
substituents). Additionally, the same anthraquinone derivative can have multiple mechanisms of action which makes it
difficult for bacteria to develop resistances.
Acknowledgements The support of [Link] (UID/DTP/04138/2013) from Fundação para a Ciência e a Tecnologia (FCT),
Portugal, is gratefully acknowledged.
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