Prenylated Xanthones as Potential Antiplasmodial

Substances
Original Paper

Abstract

potent antiplasmodial activity. Some structure-activity relationships are proposed.

Mangostin, the major xanthone of Garcinia mangostana, and a

series of synthetic derivatives were investigated for their in
vitro antiplasmodial activity against Plasmodium falciparum.
Mangostin itself showed moderate activity, but prenylated xanthones containing alkylamino functional groups exhibited quite

Introduction

912

Wilawan Mahabusarakam1
Kunnika Kuaha2
Prapon Wilairat3
Walter C. Taylor4

Malaria is still one of several tropical diseases with serious effects on humans, with 300 million people affected worldwide
annually and over one million deaths of children in Africa alone,
every year [1]. It is widely recognized that susceptibility of the
falciparum malaria parasite, the most virulent of the four human
parasites, to antimalarial drugs currently used for treatment of
malaria, particularly chloroquine and pyrimethamine, has decreased over recent years, and that this is one of the major causes
of the present failure to control the disease. As a result, it has become ever more important to search for new antimalarial substances. Several types of secondary metabolites have been investigated for inhibitory activity against Plasmodium falciparum [2],
[3], [4], [5], including natural xanthones [6], [7], [8] and synthetic
xanthones [9], [10]. Mangostin (1) is a major xanthone in the
fruit hulls of Garcinia mangostana. This compound has been
shown to exhibit several types of biological activities, viz. anti-

Key words
Mangostin G. mangostana Guttiferae prenylated xanthones
antiplasmodial Plasmodium falciparum

microbial [11], antioxidant [12], anti-inflammatory [13], antiHIV [14] and, recently, antimalarial [15]. This broad range of activities of mangostin prompted us to confirm its antiplasmodial
activity and to study also a series of mangostin derivatives,
some of which had already been tested for antioxidant [16] and
inhibition of eukaryote protein kinases and of a cyclic nucleotide-binding phosphatase [17].

Materials and Methods

General
Melting points were measured by a Johns melting point apparatus and are uncorrected. Infrared spectra were recorded on a
Beckman Acculab3 Infrared Spectrophotometer and recorded as
potassium bromide disks unless otherwise stated. Ultraviolet
spectra were determined on a Beckman UV/VIS Spectrophotometer (model 126) in ethanol. Proton magnetic resonance spectra

Affiliation
1
Department of Chemistry, Prince of Songkla University, Hat Yai, Songkhla, Thailand
2
Department of Immunology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen,
Thailand
3
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
4
School of Chemistry, University of Sydney, Sydney, NSW, Australia
Correspondence
W. Mahabusarakam Department of Chemistry Prince of Songkla University Hat Yai Songkhla 90112
Thailand Phone: +66-74-212-918 Fax: +66-74-212-918 E-mail: wilawan.m@psu.ac.th
Received February 22, 2006 Accepted May 12, 2006
Bibliography
Planta Med 2006; 72: 912916  Georg Thieme Verlag KG Stuttgart New York
DOI 10.1055/s-2006-947190 Published online August 10, 2006
ISSN 0032-0943

and irradiation experiments, on CDCl3 solutions unless otherwise stated, were measured with a Bruker AC-200 (200 MHz)
spectrometer. The chemical shifts are recorded in terms of ppm
with tetramethylsilane as internal reference. Mass spectra were
determined with an AEI-MS-902 spectrometer (at 70 eV). Precoated silica gel 60 GF254 (Merck; Darmstadt, Germany) was
used for thin layer chromatography. Merck silica gel 70 250
mesh was used for column chromatography.

Preparation of propanol derivative 4

A solution of mangostin (1.5 g, 3.6 mmol) in methanol (5 mL) was
added to a solution of sodium (230 mg) in methanol (5 mL). The
mixture was stirred for 15 minutes, then 3-chloropropanol (0.6
mL, 7 mmol) and sodium iodide (1.1 g, 7.1 mmol) were added.
The reaction mixture was refluxed for 24 h and then worked up.
The crude product was chromatographed on silica gel and eluted
with dichloromethane/acetone (10 : 1) to obtain 4 as a solid;
yield: 380 mg (22 %).

Preparation of epoxide derivatives 10 and 11

A solution of mangostin (5 g, 12 mmol) in dimethylformamide
(20 mL) and sodium hydride (2 g) in dimethylformamide (10
mL) was stirred at room temperature for 0.5 h. Then 1-chloro2,3-epoxypropane (2.5 mL, 31 mmol) was added. The reaction
mixture was refluxed for 6 h and then worked up. The residue
was chromatographed on silica gel and eluted with light petroleum/dichloromethane (4 : 5) to give yellow needles of 10 (yield:
0.2 g, 3 %) and 11 (yield: 1.5 g, 26 %).

1,3-Dihydroxy-6-(3-hydroxypropoxy)-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (4): m. p. 156 157 8C; UV:

lmax (log e) = 244 (4.53), 259 (4.47), 317 (4.41) nm; IR:
nmax = 3091 (b), 1645, 1596, 1465, 1434, 1292, 1206 cm-1; 1HNMR: d = 1.68 (6H, s, H-5, H-5), 1.77 (3H, s, H-4), 1.84 (3H, s,
H-4), 3.45 (2H, d, J = 7 Hz, H-1), 3.78 (3H, s, 7-OCH3), 4.11
(2H, d, J = 7 H, H-1), 5.24 (1H, bt, H-2), 5.30 (1H, bt, H-2),
6.25 (1H, s, H-4), 6.36 (1H, s, 3-OH), 6.73 (1H, s, H-5), 13.89
(1H, s, 1-OH), substituent group OCH2CH2CH2OH: 4.24 (2H, t,
J = 6 Hz, OCH2), 2.15 (2H, m, CH2), 3.92 (2H, q, CH2O), 1.98
(1H, bt, OH); MS: m/z = 468 (91), 425 (40), 413 (46), 397
(100), 365 (47), 320 (20), 307 (30); anal. calcd. for C27H32O7: C
69.2, H 6.9; found: C 69.2, H 7.0.

1-Hydroxy-3,6-bis(2,3-epoxypropoxy)-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (10): m. p. 128 130 8C; UV:

lmax (log e) = 244 (4.50), 262 (4.54), 312 (4.39), 351 (3.85) nm;
IR(CHCl3): nmax = 3389 (b), 1644, 1598, 1463, 1430 cm1; 1HNMR: d = 1.68 (6H, s, H-5, H-5), 1.81 (3H, s, H-4), 1.84(3H, s,
H-4), 3.38 (2H, d, J = 7 Hz, H-1), 3.80 (1H, s, 7-OCH3), 4.13 (2H,
d, J = 7 Hz, H-1), 5.24 (2H, bt, H-2 and H-2), 6.28 (1H, s, H-4),
6.73 (s, H-5), 13.47 (s, 1-OH), substituent group 2 OCH2CH(O)CH2: 4.02 and 4.29 (1H, dd, J = 2, 11 Hz and 1H, dd,
J = 3, 11 Hz, OCH2), 4.06 and 4.38 (1H, dd, J = 2, 11 Hz and 1H,
dd, J = 3, 11 Hz, OCH2), 3.44 (2H, m, 2 CH), 2.78 and 2.95 (1H,
dd, J = 3, 4 Hz and 1H, dd, J = 4, 10 Hz, CH2), 2.82 and 2.95 (1H,
dd, J = 3, 4 Hz and 1H, dd, J = 4, 10 Hz, CH2); MS: m/z = 522
(100), 478 (84), 466 (76), 450 (84), 437 (29), 422 (34), 408
(24), 394 (40), 374 (14), 360(15), 323 (14); anal. calcd. for
C30H34O8: C 69.0, H 6.6; found: C 69.3, H 6.8.

Preparation of amide derivatives 8 and 9

A mixture of mangostin (5 g, 12 mmol), chloroacetamide (2.28 g,
24 mmol) and potassium carbonate in acetone was stirred at
room temperature for 24 h. The reaction mixture was worked
up as usual and the residue was chromatographed on silica gel.
Elution with dichloromethane/methanol (50 : 1) and recrystallization in acetone gave 8 (yield: 0.8 g, 14 %) and (9) (yield: 0.9 g,
16 %) as yellow solids.
1,6-Dihydroxy-3-(2-amino-2-oxoethoxy)-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (8): m.p. 242 243 8C; UV: lmax
(log e) = 243 (4.49), 258 (4.46), 314 (4.36), 350 (3.81) nm; IR:
nmax = 3473, 3349, 3267 (b), 1689, 1651, 1604,1574 cm-1; 1H-NMR:
d = 1.69 (6H, s, H-5, H-5), 1.80 (3H, s, H-4), 1.83 (3H, s, H-4),
3.44 (2H, d, J = 7 Hz, H-1), 3.81 (3H, s, 7-OCH3), 4.10 (2H, d, J = 7
Hz, H-1), 5.23 (1H, bt, H-2), 5.27 (1H, bt, H-2), 6.31 (1H, s, H-4),
6.44 (1H, s, 6-OH), 6.86 (1H, s, H-5), 13.58 (1H, s, 1-OH), substituent group OCH2CONH2: 4.59 (2H, s, OCH2), 5.57 and 6.59 (2H,
2 bs, NH2); MS: m/z = 467 (70), 424 (28), 412 (40), 409 (28), 396
(100), 367 (58), 329 (30); anal. calcd. for C26H29O7N: C 66.8, H 6.3,
N 3.0; found: C 66.7, H 6.4, N 3.0.

1,3-Dihydroxy-6-(2,3-epoxypropoxy)-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (11): m. p. 148 149 8C; UV:

lmax (log e) = 244 (4.53), 259 (4.49), 315 (4.41) nm; IR:
nmax = 3306 (b), 1644, 1596, 1465, 1431 cm1; 1H-NMR:
d = 1.68 (6H, s, H-5, H-5), 1.81 (3H, s, H-4), 1.82 (3H, s, H4), 3.37 (2H, d, J = 7 Hz, H-1), 3.80 (3H, s, 7-OCH3), 4.08 (2H,
d, J = 7 Hz, H-1), 5.25 (2H, bt, H-2 and H-2), 6.29 (1H, s, H-4),
6.82 (1H, s, H-5), 13.41 (1H, s, 1-OH), substituent group OCH2CH(O)CH2 : 4.03 and 4.31 (1H, dd, J = 2, 11 Hz and 1H, dd,
J = 3, 11 Hz, OCH2), 3.41 (1H, m, CH), 2.80 and 2.94 (1H, dd,
J = 3, 4 Hz and 1H, dd, J = 4, 10 Hz, CH2); MS: m/z = 466 (38),
465 (80), 422 (58), 410 (72), 394 (100), 378 (23), 360 (23), 352
(21), 339 (29), 322 (35); anal. calcd. for C27H30O7: C 69.5, H 6.5;
found: C 69.8, H 6.8.
Preparation of hydroxy amino derivatives 19 and 20
Dimethylamine (0.5 mL) was added to a solution of epoxide derivative 11 or 10 (500 mg each) in methanol (5 mL) and the reaction mixtures were refluxed for 6 h. The solution was evaporated
to remove the solvent and excess amine. The residue was chro-

Mahabusarakam W et al. Prenylated Xanthones as Planta Med 2006; 72: 912 916

Original Paper

Isolation of mangostin and the preparation of compounds 1 3,

5 7, 12 18, 21 22 and 29 32 have been previously reported
[16].

1,3-Dihydroxy-6-(2-amino-2-oxoethoxy)-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (9): m. p. 231 233 8C; UV:

lmax (log e) = 245 (4.48), 263 (4.47), 315 (4.29) nm; IR:
nmax = 3370 (b), 3184 (b), 1661, 1609, 1585 cm1; 1H-NMR:
d = 1.68 (3H, s, H-5), 1.76 (3H, s, H-5), 1.84 (6H, s, H-4, H-4),
3.48 (2H, d, J = 7 Hz, H-1), 3.82 (3H, s, 7-OCH3), 4.15 (2H, d,
J = 7 Hz, H-1), 5.23, (1H, bt, H-2), 5.27 (1H, bt, H-2), 6.42 (1H,
s, 3-OH), 6.30 (1H, s, H-4), 6.75 (1H, s, H-5), 13.66 (1H, s, 1-OH),
substituent group: OCH2CONH2 4.62 (2H, s, OCH2), 5.70 and 6.75
(2H, 2 bs, NH2); MS: m/z = 467 (76), 424 (100), 412 (46), 396
(76), 368 (26); anal. calcd. for C26H29O7N: C 66.8, H 6.3, N 3.0;
found: C 66.5, H 6.5, N 2.8.

913

matographed on silica gel. Elution with dichloromethane and

methanol mixtures gave 19 and 20.

Original Paper
914

1,3-Dihydroxy-6-(2-hydroxy-3-N,N-dimethylaminopropoxy)-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (19): m. p.
148 149 8C; UV: lmax (log e) = 244 (4.53), 259 (4.49), 315 (4.41)
nm; IR: nmax = 3306 (b), 1644, 1596, 1571,1465 cm1; 1H-NMR:
d = 1.69 (3H, s, H-5), 1.81 (3H, s, H-5), 1.82 (6H, s, H-4, H-4),
3.35 (2H, d, J = 7 Hz, H-1), 3.80 (3H, s, 7-OCH3), 4.08 (2H, d, J = 7
Hz, H-1), 5.20 (1H, bt, H-2), 5.26 (1H, bt, H-2), 6.29 (1H, s, H-4),
6.82 (1H, s, H-5), 13.42 (1H, s, 1-OH), substituent group OCH2CH(OH)CH2N(CH3)2: 4.04 (2H, m, OCH2), 4.14 (1H, m, CH), 2.52,
and 2.62 (2H, 2 dd, CH2), 2.39 [6H, s, N(CH3)2]; MS: m/z = 511
(12), 410 (5), 339 (9), 102 (11), 58 (100).
1-Dihydroxy-3,6-bis(2-hydroxy-3-N,N-dimethylaminopropoxy)7-methoxy-2, 8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one (20):
m. p. 98 101 8C; UV: lmax (log e) = 312 (2.77), 265 (2.93), 247
(2.86) nm; IR: nmax = 3420, 2900, 1710,1620, 1580, 1450, 1260
cm1; 1H-NMR: d = 1.67 (6H, s, H-5, H-5), 1.80 (3H, s, H-4),
1.85 (3H, s, H-4), 3.35 (2H, d, J = 7 Hz, H-1), 3.80 (3H, s, 7OCH3), 4.12 (2H, d, J = 7 Hz, H-1), 5.20 (1H, bt, H-2), 5.23 (1H,
bt, H-2), 6.30 (1H, s, H-4), 6.72 (1H, s, H-5), 13.45 (1H, s, 1-OH),
substituent group 2 OCH2CH(OH)CH2N(CH3)2: 4.04 4.20 (6H,
m, 2 OCH2 and 2 CH), 2.51 and 2.62 (4H, 2 m, 2 CH2), 2.35
[6H, s, 2 N(CH3)2]; MS: m/z = 613 (37), 612 (89), 511 (18), 353
(8), 323 (12), 102 (27), 58 (100).
Preparation of ammonium salts 23 27
Hydrogen chloride was passed into methanolic solutions of 14,
15, 16, 17 or 21 (0.5 g each) for 15 min and the solutions were further stirred for 3 h. After removal of the solvent, the residues
were stirred with acetone for 15 min to wash out excess hydrogen chloride. Yellow solids of 23 (yield: 504 mg), 24 (yield: 510
mg), 25 (yield: 512 mg), 26 (yield: 507 mg) and 27 (yield: 501
mg) were collected by filtration.
Preparation of amino derivative 28
A solution of 3-isomangostin (1 g, 2.4 mmol) in dimethylformamide (2 mL) and sodium hydride (0.3 g) in dimethylformamide
(2 mL) was stirred at room temperature for 0.5 h. Then N,N-diethylaminoethyl chloride hydrochloride (0.5 mL, 6 mmol) was
added. The reaction mixture was refluxed for 6 h and then
worked up. The residue was chromatographed and eluted with
light petroleum/dichloromethane (4 : 5) to give yellow needles
of 28; yield: 681 mg (67 %).
5-Hydroxy-9-(2-N,N-diethylaminoethoxy)-8-methoxy-7-(3-methylbut-2-enyl)-2,2-dimethylpyrano[3,2-b]xanthen-6-one (28):
m. p. 110 112 8C; UV: lmax (log e) = 356 (3.97), 319 (4.43), 261
(4.54), 245 (4.51) nm; IR: nmax = 3420 (b), 2980, 1640, 1600 cm1;
1
H-NMR: d = 1.35 [6H, s, 2-(CH3)2], 1.65 (3H, s, H-5), 1.84 (3H,
s, H-4), 1.84 (2H, t, J = 7 Hz, H-4), 2.71 (2H, t, J = 7 Hz, H-3),
3.78, (3H, s, 8-OCH3), 4.12 (2H, d, J = 7 Hz, H-1), 5.22 (1H, bt,
H-2), 6.22 (1H, s, H-12), 6.65 (1H, s, H-10), 13.75 (1H, s, 5-OH),
substituent group OCH2CH2N(CH2CH3)2 : 4.19 (2H, t, J = 7 Hz,
OCH2), 3.00 (2H, t, J = 7 Hz, CH2), 2.71 (4H, q, 2 NCH2), 1.12
(6H, t, 2 CH3); MS: = m/z 509 (13), 410 (3), 367 (10), 295 (3),
86 (100).

Preparation of formyl derivative 33

Sodium hydroxide (2 g) in methanol (12 mL) was added dropwise to a solution of mangostin (500 mg, 1.2 mmol) in 98 % formic acid (8 mL). The mixture was stirred at room temperature
for 4 h, then diluted with water and partitioned with ether. The
ether layer was separated and washed with 10 % sodium carbonate solution and water. The dried solution was concentrated
and cooled down. The yellow precipitate was collected and chromatographed on silica gel; elution with dichloromethane gave
33, which was recrystallized from methanol to form yellow needles; yield: 140 mg (25 %).
5,9-Dihydroxy-8-methoxy-7-(3-formoxy-3-methylbutyl)-2,2-dimethylpyrano[3,2-b]xanthen-6-one (33): m. p. 175 177 8C; UV:
lmax (log e) = 242 (4.52), 256 (4.46), 319 (4.43) nm; IR:
nmax = 3371 (b), 3198, 1723, 1645, 1600 cm1; 1H-NMR:
d = 1.37 [6H, s, 2-(CH3)2], 1.63 (6H, s, H-4, H-5), 1.83 (2H, t,
J = 7 Hz, H-3), 2.05 (2H, m, H-2), 2.70 (2H, t, J = 7 Hz, H-4),
3.45 (2H, m, H-1), 3.84 (3H, s, 8-OCH3), 6.23 (1H, s, H-12), 6.51
(1H, bs, 9-OH), 6.82 (1H, s, H-10), 8.18 (1H, s, O = CH), 13.81
(1H, s, 5-OH); MS: m/z = 456 (8), 410 (83), 395 (80), 381 (62),
367 (100), 355 (66), 339 (78), 329 (25); anal. calcd. for
C25H28O8: C 66.8, H 6.2; found: C 66.2, H 6.4.
Preparation of derivatives 34 and 35
Mangostin (500 mg) in methanol (2 mL) was cooled in dry ice/
acetone and treated with a stream of ozone for 40 min, then reduced with sodium borohydride (50 mg). After stirring for an
hour, the reaction mixture was worked up. The crude residue
was chromatographed on silica gel and eluted with dichloromethane/methanol (10 : 1) to give a yellow solid of 34 (yield: 94 mg,
22 %) and 35 (yield: 146 mg, 33 %).
1,3,6-Trihydroxy-7-methoxy-2-(2-hydroxyethyl)-8-(2-oxoethyl)9H-xanthen-9-one (34): m. p. 222 224 8C; UV: lmax (log e) = 242
(4.34), 257 (4.36), 321 (4.45) nm; IR: nmax = 3259, 1698, 1647,
1611, 1580, 1466 cm1; 1H-NMR (CDCl3 + DMSO-d6): d = 2.98
(2H, t, J = 7 Hz, H-1), 3.78 (3H, s, OCH3), 3.88 (2H, t, J = 7 Hz,
H-2), 4.42 (2H, s, H-1), 4.67 (1H, bs, OH), 6.36 (1H, s, H-4), 6.90
(1H, s, H-5), 9.90 (1H, s, O = CH), 10.0 (1H, bs, OH), 10.25 (1H, bs,
OH), 13.48 (1H, s, 1-OH); MS: m/z = 360 (43), 342 (15), 329 (100),
311 (30), 301 (87), 286 (20), 271 (18), 257 (21); HR-MS: m/z =
360.0760 (M+), calcd. for C18H16O8: 360.0845.
1,3,6-Ttrihydroxy-7-methoxy-2,8-bis(2-hydroxyethyl)-9H-xanthen9-one (35): m. p. 231 233 8C; UV: lmax (log e) = 242 (4.51), 256
(4.42), 317 (4.37) nm; IR: nmax = 3161, 1644, 1602, 1568 cm1; 1HNMR (CDCl3 + DMSO-d6): d = 2.76 (2H, t, J = 7 Hz, H-1), 3.45
(2H, t, J = 7 Hz, H-1), 3.65 (3H, s, 7-OCH3), 3.65 (2H, t, J = 7 Hz,
H-2, H-2), 4.55 (1H, bs, OH), 6.15 (1H, s, H-4), 6.63 (1H, s, H-5),
9.94 (1H, s, OH), 10.09 (1H, s, OH), 13.57 (1H, s, 1-OH); MS: m/z =
362 (28), 344 (30), 329 (22), 313 (100), 297 (35), 344 (30); anal.
calcd. for C18H18O8: C 59.7. H 5.0; found: C 59.7, H 4.9.
In vitro assessment of antimalarial activity
The procedure for in vitro antiplasmodial testing of drugs against
P. falciparum-infected erythrocytes was a modification of the
[3H]-hypoxanthine incorporation method of Desjardins et al.
[18]. In brief, 200 mL aliquots of 5 % human red cell suspension
containing 1.0 % parasitemia of P. falciparum K1 (chloroquine-

Mahabusarakam W et al. Prenylated Xanthones as Planta Med 2006; 72: 912 916

Results
Drugs generally demonstrate their biological activities directly
but sometimes only give rise to active substances after being metabolized. Numerous phenolics have applications as drugs, the
phenolic group being one that can be easily metabolized. Mangostin (1) has two reactive phenolic hydroxy groups; these
groups may act as active groups in their own right, or an active
metabolite may be produced through derivatization. Functionalization of the phenolic groups was therefore an attractive objective and this was carried out to produce compounds 2 32. To
test whether the prenyl side chain of mangostin might be involved in its biological activity, derivatives 33 35 were also prepared. The structures of all derivatives were confirmed by spectroscopic and analytical data.
Mangostin (1) and its derivatives (2 35) were tested in vitro
against Plasmodium falciparum strain K1 (chloroquine- and pyrimethamine-resistant). The activity of each compound was determined as the concentration required to inhibit malaria parasite
growth by 50 % (IC50), and the results are shown in Table 1. Mangostin (1) inhibited parasite proliferation with an IC50 of 17 mM.
Derivatives with a methoxy group (2), acyl group (3) and alkylcyano groups (12 and 13) at one or both hydroxy groups showed
a decrease in activity (IC50 >17 mM). Dihydroxypropyl derivatives
(6 and 7) did not have enhanced activity, whereas a dihydroxypropyl group attached at 6-OH (5) increased the activity
(IC50 = 7.4 mM). Substitution with a hydroxypropyl group (4) resulted in a comparable activity (IC50 = 5.3 mM). The carbamide
derivatives (8 and 9) showed significant activity (IC50 = 4.5 and
8.3 mM, respectively). The greatest activity was observed with
derivatives with alkylamino groups (14 22) (IC50 < 1 mM). In order to improve the solubility of these derivatives, the hydrochloride salts (23 27) were also tested but their activities did not
change significantly. Cyclization of the prenyl side-chain (28
31) of the active amino derivatives substantially decreased the
activity (IC50 > 2 mM). In contrast, reduction of activity did not occur in the case of cyclized derivative 32 (IC50 = 0.6 mM). Disruption of the prenyl side-chains of mangostin (33 35) also resulted
in a marked reduction of antiplasmodial activity (IC50 > 20 mM).

Table 1

In vitro activity of mangostin and its derivatives against P. falciparum

Compound

Substituents

IC50 (mM)
Mean  SD

R = R = H (mangostin)

17

R = R = CH3

> 20

R = H, R = COCH3

> 20

R = CH2CH2CH2OH, R = H

5.3

 0.3

R = H, R = CH2CH(OH)CH2OH

7.4

 0.3

1

R = CH2CH(OH)CH2OH, R = H

16

R = R = CH2CH(OH)CH2OH

> 18

R = H, R = CH2CONH2

4.5

R = CH2CONH2, R = H

8.3

 0.4

10

R = R = CH2CH(O)CH2

6.1

 0.3

1
 0.3

11

R = CH2CH(O)CH2, R = H

13

1

12

R = R = CH2CH2CH2C:N

18

1

13

R = CH2CH2CH2C:N, R = H

21

2

14

R = CH2CH2N(CH2CH3)2, R = H

15

R = R = CH2CH2N(CH2CH3)2

1.5

16

R = CH2CH2N(CH3)2, R = H

0.60  0.03

17

R = CH2CH2 CH2N(CH3)2, R = H

0.10  0.01

18

R = CH2CH(OH)CH2N(CH2CH3)2, R = H

0.050  0.005

19

R = CH2CH(OH)CH2N(CH3)2, R = H

0.60  0.03

20

R = R = CH2CH(OH)CH2N(CH3)2

0.60  0.03

21

R = CH2CH(OH)CH2NHCH(CH3)2, R = H

0.60  0.03

22

R = R = CH2CH(OH)CH2NHCH(CH3)2

0.70  0.03

23

Hydrochloride salt of 14

0.75  0.03

24

Hydrochloride salt of 15

0.50  0.02

25

Hydrochloride salt of 16

2.5

26

Hydrochloride salt of 17

0.75  0.03

27

Hydrochloride salt of 21

4.8

28

R = CH2CH2N(CH2CH3)2

>2

29

R = CH2CH2N(CH3)2

>2

30

R = CH2CH2CH2N(CH3)2

>2

31

R = CH2CH(OH)CH2 N(CH3)2

6.0

32

R = CH2CH(OH)CH2 N(CH2CH3)2

0.60  0.02

chloroquine

Original Paper

and pyrimethamine-resistant) strain [19] at early ring stage were

incubated with 25 mL of compound-containing medium at the
required concentrations (compounds were initially dissolved in
DMSO and the final concentration of DMSO was 0.01 % which
did not affect parasite growth) in 96-well microtiter plates under
candle jar conditions for 24 h at 37 8C prior to the addition of
25 mL of 0.5 mCi [3H]-hypoxanthine (specific activity of 28.0 Ci/
mmol, Amersham; Buckinghamshire, UK). After a further incubation for 18 h, parasites were harvested from each well onto
glass fiber filters (Whatman grade 934 AH; Whatman; Maidstone, UK), and lysed with distilled water. The radioactivity on
the filter discs was then determined in a liquid scintillation
counter (Beckman model LS-1801; Beckman; Fullerton, CA,
USA). The IC50 values (50 % inhibition of radioactivity incorporation compared to control) were obtained from the drug dose-response curves. Each in vitro assessment was conducted in triplicate and the results were expressed as means  SD. Chloroquine
was used as control drug for comparison.

0.30  0.02
 0.1

 0.1
 0.3

 0.3

0.59  0.02

33

> 22

34

> 28

35

> 28

Mahabusarakam W et al. Prenylated Xanthones as Planta Med 2006; 72: 912 916

915

Discussion

Original Paper
916

The results of this study have shown that although mangostin

had a moderate antiplasmodial activity in the in vitro test model
used, modifications of the mangostin structure could have major
effects on antiplasmodial activity in some cases. From the structure-activity point of view, some features can be pointed out. The
best activity was achieved by the addition of alkylamino or hydroxyalkylamino groups to either one or both phenolic hydroxy
groups (14 22). Unfortunately, the number of compounds was
too small to differentiate the effects of types and number of carbons in the amino chain. Nevertheless, the IC50 values of 14, 16
19, 21 compared to those for 28 31 suggest that the presence of
3-OH and C-2-prenyl side-chain help in enhancing the antiplasmodial activity of prenylated xanthones.
The mechanism of inhibition of P. falciparum growth by mangostin and its derivatives is not clear at this stage. However, it has
been suggested that hydroxyxanthones exert their antiplasmodial activity through formation of soluble complexes with heme
thereby inhibiting parasite hemozoin formation, a process by
which the malaria parasite protects itself against the toxic effects
of heme released following digestion of hemoglobin [9], [15].
Furthermore, it has already been observed with simple xanthones that attachment of alkyl groups at positions 3 and 6 with
protonatable nitrogen atoms for ionic interaction with heme propionate groups and for targeting to the malaria parasite acidic digestive vacuole increased the antiplasmodial activity of hydroxyxanthones [10], [15]. It remains to be shown whether mangostin, as a prenylated hydroxyxanthone, and its alkylamino derivatives act by a similar mechanism. A recent study of 22 antimalarial xanthones from Calophyllum caledonicum and Garcinia
vieillardii showed that the most active compounds were those
oxygenated in the 1,3,7-positions and prenylated in the 2- and
8-positions [20]. Moreover, oxygenated xanthones have been
shown to possess in vivo antimalarial activity in a rodent model
of malaria [21].

Acknowledgements
This work was supported by the International Foundation for Science (Sweden). PW is a Senior Research Scholar of the Thailand
Research Fund.

References
1

Guerin P, Olliaro JP, Nosten F, Druilhe P, Laxminarayan R, Binka F et al.

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Inf Dis 2002; 2:
564 73

Liu M, Wilairat P, Croft SL, Tan ALC, Go ML. Structure-activity relationships of antileishmanial and antimalarial chalcones. Bioorg Med
Chem, 2003: 2729 38
3
Iwasa K, Nishiyama Y, Ichimaru M, Moriyasu M, Kim HS, Wataya Y et
al. Structure-activity relationships of quaternary protoberberine alkaloids having an antimalarial activity. Eur J Med Chem 1999; 34: 1077
83
4
Campell WE, Gammon DW, Smith P, Abrahams M, Purves TD. Composition and antimalarial activity in vitro of the essential oil of
Tetradenia riparia. Planta Med 1997; 63: 270 2
5
Murakami N, Mostaqul HM, Tamura S, Itakaki S, Horii T, Kobayashi M.
New antimalarial flavonol glycoside from Hydrangeae dulcis folium.
Bioorg Med Chem Lett 2001; 11: 2445 7
6
Likhitwitayawuid K, Chanmahasathien W, Ruangrungsi N, Krungkrai J.
Xanthones with antimalarial activity from Garcinia dulcis. Planta Med
1998; 64: 281 2
7
Likhitwitayawuid K, Phadungcharoen T, Krungkrai J. Antimalarial xanthones from Garcinia cowa. Planta Med 1998; 64: 70 2
8
Isaka M, Jaturaput A, Rukseree K, Danwisetkanjana K, Tanticharoen M,
Thebtaranonth Y. Phomoxanthones A and B, novel xanthone dimers
from the endophytic fungus Phomopsis species. J Nat Prod 2001; 64:
1015 8
9
Ignatushchenko MV, Winter RW, Baechinger HP, Hinrichs DJ, Riscoe
MK. Xanthones as antimalarial agents: studies of a possible mode of
action. FEBS Lett 1997; 409: 67 73
10
Kelly JX, Winter R, Peyton DH, Hinrichs DJ, Riscoe M. Optimization of
xanthones for antimalarial activity: the 3,6-bis-w-diethylaminoalkoxyxanthone series. Antimicrob Agents Chemother 2002; 46: 144 50
11
Mahabusarakam W, Wiriyachitra P, Phongpaichit S. Antimicrobial activities of chemical constituents from Garcinia mangostana L. J Sci Soc
Thailand 1986; 12: 239 42
12
Williams P, Ongsakul M, Proudfoot J, Croft KD, Beilin L. Mangostin inhibits the oxidative modification of human low density lipoprotein.
Free Radic Res 1995; 23: 175 84
13
Gopalakrishnan C, Shankaranarayanan D, Kameswaran L, Nazimudeen
SKPG. Effect of mangostin, a xanthone from Garcinia mangostana Linn.
in immunopathological and inflammatory reactions. Indian J Exp Biol
1980; 18: 843 6
14
Vlietinck AJ, De Bruyne T, Apers S, Pieters LA. Plant-derived leading
compounds for chemotherapy of human immunodeficiency virus
(HIV) infection. Planta Med 1998; 64: 97 109
15
Riscoe M, Kelly JX, Winter R. Xanthones as antimalarial agents: discovery, mode of action and optimization. Curr Med Chem 2005; 12:
2539 49
16
Mahabusarakam W, Proudfoot J, Taylor WC, Croft K. Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin.
Free Radic Res 2000; 33: 643 59
17
Lu XZ, Hasmeda M, Mahabusarakam W, Ternai B, Ternai PC, Polya GM.
Inhibition of eukaryote protein kinases and of a cyclic nucleotidebinding phosphatase by prenylated xanthones. Chem Biol Interact
1998; 114: 121 40
18
Desjardins RE, Canfield CJ, Haynes JD, Chulay JC. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 1979; 16: 710 8
19
Thaithong S, Beale GH. Resistance of ten Thai isolates of Plasmodium
falciparum to chloroquine and pyrimethamine by in vitro tests. Trans
R Soc Trop Med Hyg 1981; 75: 271 3
20
Hay AE, Helesbeux JJ, Duval O, Labaied M, Grellier P, Richomme P. Antimalarial xanthones from Calophyllum caledonicum and Garcinia
vieillardii. Life Sci 2004; 75: 3077 85
21
Fotie J, Nkengfack AE, Rukunga G, Tolo F, Peter MG, Heydenreich M. Invivo antimalarial activity of some oxygenated xanthones. Ann Trop
Med Parasitol 2003; 97: 683 8

Mahabusarakam W et al. Prenylated Xanthones as Planta Med 2006; 72: 912 916