Antimicrobial activities of the bromophenols from the red alga Odonthalia corymbifera and some synthetic derivatives

Article abstract of DOI:10.1016/j.bmcl.2007.11.003

A series of bromophenols was obtained by isolation from red alga Odonthalia corymbifera and by reactions of bis(hydroxyphenyl)methanes with bromine. New bromophenols including 3,3′,5,5′-tetrabromo-2,2′,4,4′-tetrahydroxydiphenylmethane (10), a regioisomer of the potent antimicrobial natural product, together with known derivatives were synthesized in high yield. All of the isolated and synthesized compounds were tested for antimicrobial activity against Gram-negative, Gram-positive bacteria and fungi. The preliminary structure-activity relationship, to elucidate the essential structure requirements for antimicrobial activity, has been described. Among the isolated natural products 2,2′,3,3′-tetrabromo-4,4′,5,5′-tetrahydroxydiphenylmethane (4) was found to be the most active derivative against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, and Trichophyton mentagrophytes. The synthetic bromophenols 3,3′-dibromo-6,6′-dihydroxydiphenylmethane (13) and 3,3′,5,5′-tetrabromo-6,6′-dihydroxydiphenylmethane (14) showed potent antibacterial effect against Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Proteus vulgaris, and Salmonella typhimurium.

Full text of DOI:10.1016/j.bmcl.2007.11.003

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 104–108
Antimicrobial activities of the bromophenols from the red alga
Odonthalia corymbifera and some synthetic derivatives
Ki-Bong Oh,a Ji Hye Lee,b Soon-Chun Chung,a Jongheon Shin,c Hee Jae Shin,b
Hye-Kyeong Kimd,* and Hyi-Seung Leeb,*
aDepartment of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
bMarine Natural Products Laboratory, Korea Ocean Research & Development Institute, Ansan PO Box 29,
Seoul 425-600, Republic of Korea
cNatural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 110-460, Republic of Korea
dDepartment of Food Science & Nutrition, The Catholic University of Korea, Bucheon 420-743, Republic of Korea
Received 12 August 2007; revised 18 October 2007; accepted 1 November 2007
Available online 5 November 2007
Abstract—A series of bromophenols was obtained by isolation from red alga Odonthalia corymbifera and by reactions of
bis(hydroxyphenyl)methanes with bromine. New bromophenols including 3,30,5,50-tetrabromo-2,20,4,40-tetrahydroxydiphenylme-
thane (10), a regioisomer of the potent antimicrobial natural product, together with known derivatives were synthesized in high
yield. All of the isolated and synthesized compounds were tested for antimicrobial activity against Gram-negative, Gram-positive
bacteria and fungi. The preliminary structure–activity relationship, to elucidate the essential structure requirements for antimicro-
bial activity, has been described. Among the isolated natural products 2,20,3,30-tetrabromo-4,40,5,50-tetrahydroxydiphenylmethane
(4) was found to be the most active derivative against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, and Trichophy-
ton mentagrophytes. The synthetic bromophenols 3,30-dibromo-6,60-dihydroxydiphenylmethane (13) and 3,30,5,50-tetrabromo-6,
60-dihydroxydiphenylmethane (14) showed potent antibacterial effect against Staphylococcus aureus, Bacillus subtilis, Micrococcus
luteus, Proteus vulgaris, and Salmonella typhimurium.
Ó 2007 Elsevier Ltd. All rights reserved.
Bromophenol compounds have been frequently encoun-
tered in various marine organisms including red algae,
brown algae, ascidians, and sponges. Especially, the
red algae of the family Rhodomelaceae are known as a
rich source of bromophenols.1–17 Some of these com-
pounds previously isolated from the family exhibited a
wide spectrum of pharmacological activities such as en-
zyme inhibition,3,9 cytotoxic,4 antioxidant,8 feeding-
deterrent,10 anti-inflammatory,11 and antimicrobial13
activities.
the crude extract using a variety of chromatographic
techniques afforded several bromophenol compounds.18
Based upon the results of combined spectral analyses,
the metabolites were identified to be 4-(2-aminoethyl)-
2,6-dibromophenol (1),19,20 2,3-dibromo-4,5-dihydr-
oxybenzyl alcohol (2),10 2,3-dibromo-4,5-dihydroxybenzyl
methyl ether (3),17 2,20,3,30-tetrabromo-4,40,5,50-tetra-
hydroxydiphenylmethane (4),15 2,20,3-tribromo-30,4,40,
5-tetrahydroxy-60-hydroxymethyl diphenylmethane (5),6
and
3-bromo-4-(2,3-dibromo-4,5-dihydroxybenzyl)-5-
methoxymethylpyrocatechol (6) (Fig. 1).15
In the course of our search for biologically active
constituents from marine algae, we collected Odonthalia
corymbifera, (family, Rhodomelaceae), whose crude
extract exhibited moderate antimicrobial activity against
various microorganisms. Bioassay-guided separation of
The in vitro antimicrobial activities of the bromophenols
1–6were assessed against three representative Gram-posi-
tive bacteria viz. Staphylococcus aureus (ATCC6538p),
Bacillus subtilis (ATCC 6633), and Micrococcus luteus
(IFC 12708), three Gram-positive bacteria viz. Proteus
vulgaris (ATCC3851), Salmonella typhimurium (ATCC
14028), and Escherichia coli (ATCC 25922), and four fun-
gal organisms viz. Candida albicans (ATCC10231),
Aspergillus fumigatus (HIC6094), Trichophyton rubrum
(IFO 9185), and Trichophyton mentagrophytes (IFO
Keywords: Bromophenol; Red alga; Structure–activity relationship;
Antimicrobial.
*
Corresponding authors. Tel.: +82 31 400 6179; fax: +82 31 400 6170
(H.-S.L.); e-mail: hslee@kordi.re.kr
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.003

K.-B. Oh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 104–108
105
OR
OR
Br
Br
NH2
Br
Br
Br
Br
Br
Br
Br
HO
OH
Br
OH
HO
Br
OH
OH
OH
OH
OH
OH
OH
1
2 R = H
3 R = CH3
5 R = H
6 R = CH3
4
Figure 1. Bromophenols from Odonthalia corymbifera.
40996).21,22 Data for the metabolites are presented in
Tables 1 and 2 as the minimal inhibitory concentration
(MIC). Among the isolated natural products compound
4 was found to be the most active derivative against
C. albicans, A. fumigatus, T. rubrum, andT. mentagrophytes.
Specially, the di-phenolic metabolites 4–6 display good
inhibition activity against Gram-positive and Gram-neg-
ative organisms except E. coli, whereas the mono-pheno-
lic metabolites 1–3 showed no antibacterial activities
(Table 1). However, this trend does not translate exactly
Table 1. Antibacterial activity
Compound
Antibacterial activity (MIC, lg/ml)
S. aureus
B. subtilis
M. luteus
P. vulgaris
S. typhimurium
E. coli
1
100
>100
>100
>100
25
>100
>100
>100
25
>100
>100
>100
50
>100
>100
>100
50
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
12.5
2
>100
>100
25
3
4
5
50
25
100
25
50
25
100
25
100
25
6
7
>100
>100
>100
25
>100
>100
>100
25
>100
>100
>100
25
>100
>100
>100
25
>100
>100
>100
25
8
10
12
13
3.12
1.56
25
3.12
1.56
12.5
6.25
>100
1.56
1.56
1.56
12.5
6.25
>100
1.56
3.12
1.56
25
3.12
3.12
25
14
16
17
18
12.5
>100
1.56
6.25
>100
3.12
6.25
>100
3.12
Ampicillin
Microorganisms: Staphylococcus aureus ATCC6538p; Bacillus subtilis ATCC 6633; Micrococcus luteus IFC 12708; Proteus vulgaris ATCC3851;
Salmonella typhimurium ATCC 14028; Escherichia coli ATCC 25922.
Table 2. Antifungal Activity
Compound
Antifungal activity (MIC, lg/ml)
C. albicans
A. fumigatus
T. rubrum
T. mentagrophytes
1
100
>100
100
>100
>100
>100
0.78
>100
50
>100
50
2
3
12.5
1.56
50
12.5
1.56
50
4
1.56
100
5
>100
25
6
25
25
25
7
>100
>100
>100
>100
>100
>100
>100
>100
>100
6.25
>100
>100
>100
>100
>100
>100
>100
>100
>100
3.12
>100
>100
>100
>100
>100
>100
>100
>100
>100
3.12
>100
>100
>100
>100
>100
>100
>100
>100
>100
3.12
8
10
12
13
14
16
17
18
Amphotericin B
Microorganisms: Candida albicans ATCC10231; Aspergillus fumigatus HIC6094; Trichophyton rubrum IFO 9185; Trichophyton mentagrophytes IFO
40996.

106
K.-B. Oh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 104–108
to antifungal activities. As shown in Table 2, mono-phe-
nolic compound 3 also showed moderate levels of inhibi-
tion toward some fungi.
6,60-dihydroxydiphenylmethane (13) in 41% and 53%
yields, respectively.27 The 3,30,5,50-tetrabromo-6,60-
dihydroxydiphenylmethane (14)28 was prepared by the
reaction of the same reactant with excess of bromine
in acetic acid as a solvent to increase the solubility of
the intermediates in excellent yield (Scheme 3). As
shown in Scheme 4, the other bromophenols, 3,30-dibro-
mo-4,40-dihydroxydiphenylmethane (16), 3,30,5-trib-
romo-4,40-dihydroxydiphenylmethane (17), and
3,305,50-tetrabromo-4,40-dihydroxydiphenylmethane (18),29
were also synthesized from bis(4-hydroxyphenyl)meth-
ane (15) in the same manner. All of the strongly acti-
vated phenols 9, 11, and 15 toward electrophilic
aromatic substitution reacted readily with bromine to
afford various bromophenols just as expected.
In order to examine modifications of the bioactive bro-
mophenol via chemical transformations, hydrodehalo-
genation reactions of natural products 4 and 5 were
carried out23 as shown in Scheme 1. The reactions of
the bromophenols 4 and 5 with H2 gas in the presence
of Pd/Al2O3 and triethylamine in methanol gave corre-
sponding debrominated phenolic compounds 724 and
8, respectively. The transformed phenolic compounds
7 and 8 were also evaluated for in vitro antimicrobial
activities toward various microorganisms. The results
are added in Tables 1 and 2. According to the data
shown in the Tables, compounds 7 and 8 were found
to be completely inactive against Gram-negative,
Gram-positive bacteria and fungi.
The seven analogues prepared by these bromination reac-
tions were also tested for antibacterial and antifungal
activities. The minimum inhibitory concentrations of
antibacterial and antifungal activity are summarized in
Tables 1 and 2, respectively. The underlying reasons for
the antimicrobial properties of natural and synthetic
bromophenols are not well understood. Disappointedly,
we did not observe any antibacterial or antifungal activity
by analogue 10, which is only a regioisomer of the potent
These results revealed that the di-phenolic backbone and
the presence of one or more bromines on the phenol ring
are important for antimicrobial activity. Therefore, the
focus of the continued study was to demonstrate that
the number and position of bromines in bromophenols
could influence potency against microorganisms. The
bromophenol analogues have been synthesized as shown
in Schemes 2–4.25
OH
Br
OH
Br
To investigate the positional effects of bromines on the
phenol ring on the antibacterial activity, the analogue
3,30,5,50-tetrabromo-2,20,4,40-tetrahydroxydiphenylme-
thane (10) was synthesized by the reaction of phenolic
compound 9,26 prepared by the reduction from the cor-
responding benzophenone, with excess of bromine in
acetic acid in 90% yield (Scheme 2). Similarly, treatment
of bis(2-hydroxyphenyl)methane (11) with two equiva-
lents of bromine in the mixture of acetic acid and
CH2Cl2 gave the mixture of bromophenols 3-bromo-
20,6-dihydroxydiphenylmethane (12) and 3,30-dibromo-
OH
OH
Br
Br
b
11
14
a
OH
Br
OH
OH
Br
OH
Br
+
13
12
R
Scheme 3. Bromination of bis(2-hydroxyphenyl)methane. Reagents:
(a) Br2, AcOH+CH2Cl2, (b) excess Br2, AcOH.
a
4 / 5
HO
OH
OH
OH
7 : R = H
8 : R = CH2OH
Br
Br
b
HO
OH
HO
OH
Scheme 1. Catalytic hydrodebromination. Reagents: (a) H2, Pd/Al2O3/
Et3N, MeOH.
Br
Br
15
18
a
OH
Br
OH
Br
OH
OH
Br
Br
a
Br
HO
Br
OH
Br
HO
Br
OH
+
HO
OH
HO
OH
Br
9
10
16
17
Scheme 2. Bromination of bis(2,4-dihydroxyphenyl)methane. Reagents:
(a) excess Br2, AcOH.
Scheme 4. Bromination of bis(4-hydroxyphenyl)methane. Reagents:
(a) Br2, AcOH+CH2Cl2, (b) excess Br2, AcOH.

K.-B. Oh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 104–108
107
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antifungal natural product 4. However, some of synthetic
bromophenols exhibited moderate to good antibacterial
activity with degrees of variation (Table 1). Among syn-
thetic bromophenols, compounds 13 and 14 have equally
potent activities against S. aureus, B. subtilis, M. luteus, P.
vulgaris, and S. typhimurium as ampicillin, a standard ref-
erence compound.
11. Wiemer, D. F.; Idler, D. D.; Fenical, W. Experientia 1991,
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In terms of the antifungal activity, natural bromophenol
4 showed roughly two- to fourfold lower MIC values
than the reference compound, amphotericin B. On the
other hand, replacement of position and number of hy-
droxyl group and bromine by synthesis of bromophe-
nols led to inactive compounds against C. albicans, A.
fumigatus, T. rubrum, and T. mentagrophytes (Table 2).
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21. Three Gram-negative bacteria (Escherichia coli ATCC
35218, Proteus vulgaris ATCC 3851, and Salmonella
typhimurium ATCC 14028) and three Gram-positive
bacteria (Bacillus subtilis ATCC 6633, Micrococcus luteus
IFO 12708, and Staphylococcus aureus ATCC 6538p) were
used for antimicrobial activity tests. Bacteria were grown
overnight in Luria Bertani (LB) broth at 37 °C, harvested
by centrifugation, and then washed twice with sterile
distilled water. Stock solutions of the series compound
were prepared in DMSO. Each stock solution was diluted
with Standard method broth (Difco) to prepare serial
twofold dilutions in the range of 100 to 0.8 lg/ml. Ten
microliters of the broth containing about 105 colony-
forming units (cfu)/ml of test bacteria wwasere added to
each well of a 96-well microtiter plate. Culture plates were
incubated for 24 h at 37 °C.
In conclusion, a series of bromophenols has been
prepared. The antimicrobial activity of these com-
pounds was evaluated against various Gram-positive,
Gram-negative bacteria and fungi. Among the isolated
natural products 2,20,3,30-tetrabromo-4,40,5,50-tetra-
hydroxydiphenylmethane (4) was found to be the most
active derivative against C. albicans, A. fumigatus, T. ru-
brum, and T. mentagrophytes. The synthetic bromophe-
nols 3,30-dibromo-6,60-dihydroxydiphenylmethane (13)
and
3,30,5,50-tetrabromo-6,60-dihydroxydiphenylme-
thane (14) showed potent antibacterial effect against S.
aureus, B. subtilis, M. luteus, P. vulgaris, and S. typhimu-
rium. By modifying the bromophenol substituents, we
were able to discover several compounds which had po-
tency profiles in our antimicrobial assays. Further work
on the modifying of these compounds in an expanded
series of halogenated phenol compounds will be re-
ported in due course.
Acknowledgments
22. Candida albicans ATCC 10231, Aspergillus fumigatus HIC
6094, Trichophyton rubrum IFO 9185, and Trichophyton
mentagrophytes IFO 40996 were used for antifungal
activity tests. C. albicans was grown for 48 h at 28 °C in
YPD broth (1% yeast extract, 2% peptone, and 2%
dextrose), harvested by centrifugation, and then washed
twice with sterile distilled water. A. fumigatus, T. rubrum,
and T. mentagrophytes were plated in potato dextrose agar
(PDA) (Difco) and incubated at 28 °C for 2 weeks. Spores
were washed three times with sterile distilled water and
resuspended in distilled water to obtain an initial inoculum
size of 105 spores/ml. Each test compound was dissolved in
DMSO and diluted with potato dextrose broth (Difco) to
prepare serial twofold dilutions in the range of 100 to
0.8 lg/ml. Ten microliters of the broth containing about
103 (for yeast) and 104 (for filamentous fungi) cells/ml of
test fungi was added to each well of a 96-well microtiter
plate. Culture plates were incubated for 48 ꢀ 72 h at
28 °C.
23. Experimental: The 1D and 2D NMR spectra were
obtained at 500 and 125 MHz for 1H and 13C, respectively,
on a Varian UNITY 500 spectrometer in methanol-d4
with solvent peaks as references. Mass spectra were
recorded on a ThermoFinnigan Surveyor MSQ spectrom-
eter. Column chromatography was performed with silica
gel (230-400 mesh), RP-18 reversed-phase silica gel (43-
60 lm). Typical procedure: A stirred mixture of the
bromophenol 5 (15 mg), 10% Pd/Al2O3 (7 mg), and
triethylamine (15 mg) in methanol was hydrogenated
This work was supported by the Korea Ocean Re-
search & Development Institute (PE97802), the Minis-
try of Maritime Affairs and Fisheries (PM44700), and a
Grant (20050401034619) from the BioGreen 21 Pro-
gram, Rural Development Administration, Republic
of Korea.
References and notes
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108
K.-B. Oh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 104–108
using H2 balloon at room temperature for 2 hrs. The
above procedure. 3-Bromo-20,6-dihydroxydiphenylmethane
(12): 1H NMR (CD3OD, 500 MHz) d 7.09 (1H, dd,
J = 8.77, 2.43 Hz), 7.06 (1H, d, J = 2.43 Hz), 7.03 (1H, m),
7.02 (1H, m), 6.77 (1H, m), 6.74 (1H, td, J = 7.31,
0.97 Hz), 6.67 (1H, d, J = 8.77 Hz), 3.84 (2H, s); 13C
NMR (CD3OD, 125 MHz) d 156.1, 155.5, 133.7, 131.6
(x2), 130.6, 128.4, 127.8, 120.7, 117.6, 116.0, 112.1, 30.5;
ESI(-) m/z 278 (M-H). 3,30-Dibromo-4,40-dihydroxy-
diphenylmethane (16): 1H NMR (CD3OD, 500 MHz) d
7.23 (2H, d, J = 2.19 Hz), 6.94 (2H, dd, J = 8.29, 2.19 Hz),
6.80 (2H, d, J = 8.29 Hz), 3.73 (2H, s); 13C NMR
(CD3OD, 125 MHz) d 152.4, 134.1, 132.9, 128.7, 116.0,
109.5, 38.9; ESI(-) m/z 358 (M-H). 3,30,5-Tribromo-4,40-
dihydroxydiphenylmethane (17): 1H NMR (CD3OD,
500 MHz) d 7.24 (1H, d, J = 2.39 Hz), 7.22 (2H, m), 6.93
(1H, dd, J = 8.29, 2.39 Hz), 6.81 (1H, d, J = 8.29 Hz), 3.70
(2H, s); 13C NMR (CD3OD, 125 MHz) d 152.6, 149.4,
135.8, 133.3, 133.0, 132.2 (x2), 128.8, 116.2, 111.1 (x2),
109.7, 38.5; ESI(-) m/z 436 (M-H).
reaction mixture was filtered and the filtrate was evapo-
rated to dryness. The residue was partitioned between
CH2Cl2 and H2O, and the organic layer was concentrated
to yield corresponding phenolic compound 8 quantita-
tively. 3,30,4,40-Tetrahydroxy-6-hydroxymethyldiphenylme-
thane (8): 1H NMR (CD3OD, 500 MHz) d 6.81 (1H, s),
6.65 (1H, d, J = 8.05 Hz), 6.54 (1H, s), 6.52 (1H, d,
J = 1.95 Hz), 6.45 (1H, dd, J = 8.05, 1.95 Hz), 4.42 (2H, s),
3.76 (2H, s); 13C NMR (CD3OD, 125 MHz) d 146.1,
145.1, 144.3(x2), 134.3, 132.1, 131.6, 120.9, 118.5, 117.0,
116.8, 116.2, 62.9, 37.8; APCI(-) m/z 261.0 (M-H).
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2,20,4,40-tetrahydroxydiphenylmethane (9) and bromine
(81 mg, 0.51 mmol) in 3 ml of acetic acid was stirred at
room temperature for 2 hrs. The excess of bromine was
removed by blowing with N2, and the solvent was
evaporated under reduced pressure. The crude product
was purified by RP-18 column chromatography with a
mixture of water and methanol as an eluent to afford
49 mg (0.09 mmol, 90 %) of compound 10. 3,30,5,50-
Tetrabromo-2,20,4,40-tetrahydroxydiphenylmethane (10):
1H NMR (CD3OD, 500 MHz) d 7.11 (1H, s), 3.81 (1H, s);
13C NMR (CD3OD, 125 MHz) d153.0, 150.8, 133.0, 122.7,
102.1, 101.3, 30.8; APCI(-) m/z 547.8 (M-H). All other
compounds of this series were synthesized by following the
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