Open Journal of Synthesis Theory and Applications, 2013, 2, 91-96 Published Online October 2013 (
Regioselective Synthesis and Biological Evaluation of
1-Hydroxyl Modified Ailanthinone Derivatives as
Mahendra D. Chordia*, William F. McCalmont, Kirsten S. Smith, Philip L. Smith*
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, USA
Email: *, *
Received August 20, 2013; revised September 26, 2013; accepted October 11, 2013
Copyright © 2013 Mahendra D. Chordia et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The triterpene quassinoid ailanthinone is a structurally intricate natural product possessing highly potent antimalarial
activity against multidrug resistance plasmodium parasites. Although the mechanism of action of ailanthinone is not
completely understood, it is presumed to disrupt regular ribosomal functions by inhibiting parasite protein synthesis.
Natural scarcity and low solubility of many quassinoid s h ave impeded th eir deve lopment as potential clin ical candid ates,
but exquisite potency of ailanthinone against Plasmodium remains compelling in the global fight against malaria.
Herein, we report the highly selective synthesis of 1-hydroxyl derivatives of ailanthinone, including ester, carbonate,
carbamate and sulfonate derivatives. The key feature of the synthesis is a one-step regioselective modification of the
1-hydroxyl grou p in favor of two other hydroxyl groups at C12 and C13. Der ivatives were obtain ed via direct reaction
with acyl/sulfonyl chlorides in the presence of a tertiary amine base without any protection-deprotection. In vitro anti-
malarial evaluations of these derivatives were compared with chloroquine and mefloquine against the Plasmodium fal-
ciparum clones, D6, W2, and TM91C235. The results demonstrate that modification of the 1-hydroxyl group is achiev-
able, and the antimalarial activity of these derivatives relative to the paren t product is sign ificantly retained, thus paving
the way for synthesis of derivatives with improved biological availability and/or increased potency.
Keywords: Antimalarials; Ailanthinone; Triterpenoids; Quassinoid; Plasmodium Falciparum; Multidrug Resistance
1. Introduction
Plants of the family Simaroubaceae have long been util-
ized as therapeutic material for a number of diseases be-
cause of its anti-malarial, antiviral, amoebicidal, insecti-
cidal, anti-feedent and leish manicidal properties in Africa,
Asia, and South America [1-4]. The remedial properties of
these plants materials are thought to be due to presence
of a class of compounds called quassinoids, which be-
long to the triterpene group of natural products. Several
quassinoid derivatives isolated from various plants have
exhibited significant in vitro potency against both chlo-
roquine-sensitive and chloroquine-resistant strains of
Plasmodium falciparum [5,6]. Quassinoids were first iso-
lated over 20 years ago and were initially believed to be
unsuitable for clinical development owing to their scar-
city, and later for their relatively low therapeutic indices
when administered in vivo. Recently, however, a number
of new studies have demonstrated that semi-synthetic
derivatives of quassinoids possess significant in vivo ef-
ficacy against P. berghei infections in mice [7]. Fur-
thermore, some of these compounds displayed no ob-
servable toxicity when administered at therapeutic doses
Although the mechanism of action of the quassinoid
natural products as antimalarials is not completely un-
derstood, a number of studies suggest that they act as
inhibitors of protein synthesis by disrupting normal ri-
bosomal function of the parasite. Evidence for this has
been demonstrated in cultures of P. falciparum [9].
Quassinoids, therefore, appear to function as antimalari-
als through a fundamentally different mechanism from
that of chloroqu ine and other current antimalarials. Thus,
they represent a new class of potential therapeutics that
may be less prone to the development of drug-resistance
by the parasite. Studies of quassinoids thus may offer
attractive clinical alternative to more relevant quinine
based drugs.
As part of a continuing program that encompasses the
*Corresponding authors.
opyright © 2013 SciRes. OJSTA
collaborative efforts of the Natural Products Group of
the Division of Experimental Therapeutics, WRAIR, the
Bioresources Development and Conservation Program
(BDCP), Silverspring, MD, we selected a highly promis-
ing lead quassinoid natural product, ailanthinone, that
displays exception al in vitro antimalarial activity with an
IC50 of ~2.8 ng/mL against the chlo roquine resistant W2
strain (unpublished results from in ho use screening ). This
IC50 exhibited by ailanthinone is comparable to that ob-
served for chloroquine used in controls. Furthermore,
ailanthinone retains potent anti-malarial activity (IC50 =
4.3 ng/mL) against the multidrug resistant strain of P.
falciparum TM91C235, thus providing a new window of
opportunity to develop its derivatives as potential thera-
peutic agents against malaria. However, development of
ailanthinone as an antimalarial is hampered by its natural
scarcity and poor solubility in aqueous media. With an
aim to develop structure activity relationship repertoire
and to alleviate challenges with natural availability by
improving its potency/bio-availability, we initiated stud-
ies to understand the chemical reactivity of ailanthinone.
Our initial studies focused on chemo-selective reactivity
of the various hydroxyl groups. Results o btained from th e
studies are presented here along with in vitro biological
2. Experimental Section
2.1. General Methods
Ailanthinone samples used in the current studies were
kindly provided by the International Center for Ethno
medicine and Drug Development (InterCEDD) program.
All other chemicals and solvents were procured from
standard sources such as Aldrich (St. Louise, MO) and/or
Acros Organics (Morris Plains, NJ). All chemicals pur-
chased were of the highest quality available and used
without further purification. Preparative silica gel TLC
plates were purchased from Analtech Inc. (Newark, De).
The TLC and preparative plates were monitored for de-
velopment with UV light (short wavelength 254 nm).
1H-NMR analyses were performed on Bruker Avance
300 MHz or Varian Unity 300 MHz spectrophotometers.
The chemical shifts are noted in ppm as δ values and
coupling constant are reported as J in Hz. The ESI mass
spectral data for compounds were performed on LCQ
(Thermo Finnigan) ion trap LCMS instrument equipped
with waters HPLC. Samples are prepared in HPLC grade
acetonitrile and injected in LCMS using H2O:CH3CN
formic acid (1%) solvent system in isocratic at flow rate
of 0.3 mL/min. The mass spectra were recorded in posi-
tive ion mode using following parameters: capillary tem-
perature 250˚C. ESI spay voltage 4.5 kV, multiplyer
1500 V at WRAIR’s mass-spectrometry facilities. The in
vitro antimalarial biological data was collected at in
house facilities.
2.2. Experimental Procedures
Acylation of ailanthinone with acetic anhydride: A solu-
tion of acetic anhydride (0.1 M, 300 L, 0.03 mmol) in
dry CH2Cl2 was added to premixed cold solution (4˚C) of
ailanthinone (7.2 mg, 0.015 mmol) and triethyl amine
(100.0 L, 0.72 mmol) in dry CH2Cl2 (1.0 mL). The mix-
ture was stirred for 1 hr and allowed to warm room tem-
perature and further stirred for 4 hrs. The TLC analysis
of the reaction mixture revealed formation of two new
non-polar products. The reaction mixture was diluted
with ethyl acetate (10 mL) and washed with water (5 mL)
followed by 10 % NaHCO3 (5 mL) solution. The organic
layer was finally washed with brine and dried over
Na2SO4 and concentrated under reduced pr essure to yield
crude residue. Purification of crude material by prepara-
tive TLC (Silica gel GF, 20 × 20, 250 micron) yielded
two compounds polar 1-acetyl ailanthinone (5.1 mg, 65%)
and a non-polar ring opened 1, 20-diacety seco-ailan-
thinone ( 2.2 mg, 26%) .
1H-NMR of 1-acetyl-ailanthione (4) (CDCl3): δ 0.96 (t,
J = 7.8 Hz, 3H, CH3), 0.97 (q, J = 7.2 Hz, 3H, CH3), 1.09
(d, J = 6.9 Hz, 3H, CH3), 1.18 (d, J = 6.0 Hz, 3H, CH3),
1.35 (s, 3H, C10-CH3) 1.45 (m, 1H), 1.60 (m, 1H), 1.96
(m, 1H), 1.99 (brs, 3H), 2.26 (s, 3H, COCH3), 2.35 (m,
2H), 2.42 (q, J = 6.9 Hz, 1H, CHCO), 2.62 (s, 1H), 3.16
(brd, J = 12.0 Hz, 1H), 3.56 (brd, J = 4.5 Hz, 1H), 3.68
(d, J = 9.0 Hz, 1H), 3.96 (d, J = 9.0 Hz, 1H), 4 .31 (dq, J
= Hz, 2H, OCH2) 4.63 (dd, J = 1.2, 4.8 Hz, 1H), 5.28 (s,
1H), 5.49 (brd, J = 6.0 Hz, 1H), 5.70 (s, 1H), 6.05 (q, J =
1.8 Hz, 1H, C3-H). LCMS: observed ESI m/z 543
[M+Na]+; calculated for C27H35O10Na 543.
1H-NMR of 1,20-diacetyl seco-ailanthinone (5) (CDCl3):
δ 0.94 (t, J = 7.8 Hz, 3H, CH3), 0.98 (q, J = 7.2 Hz, 3H,
CH3), 1.24 (d, J = 6.9 Hz, 3H, CH3), 1.28 (s, 3H,
C10-CH3) 1.51 (m, 1H), 1.65 (m, 1H), 1.96 (m, 1H), 1.97
(brs, 3H), 2.05 (s, 3H, COCH3), 2.08 (s, 3H, COCH3),
2.27 (m, 1H), 2.49 (m, 1H), 3.21 (brd, J = 12.3 Hz, 1H),
3.31 (s, 1H), 3.80 (d, J = 12.9 Hz, 1H, C-20H), 3.84 (d, J
= 2.4 Hz, 1H), 3.94 (s, 1H), 4.66 (d, J = 12.6 Hz, 1H,
C-20H), 4.97 (t, J = 1.8 Hz, 1H), 5.19 (s, 1H), 5.98 (d, J
= 9.0 Hz, 1H), 6.05 (q, J = 1.2 Hz, 1H, C3-H). LCMS:
observed ESI m/z 585 [M+Na]+; calculated for
C29H38O11Na 585.
General procedure for modification of 1-hydroxyl
Ailanthinone (3) (5.0 mg, 0.0105 mmol) was dissolved
in CH2Cl2 (1.0 mL) and to it was added triethylamine
(50.0 L, 0.36 mmol) and cooled in ice bath. Subsequently
the acyl chloride reagent (0.01 mmol, from freshly made
1 mM solution in CH2Cl2) was added. The mixture was
stirred at 5˚C for 1hr and then allowed to warm to room
temperature (4 - 16 hrs). The reaction was followed by
Copyright © 2013 SciRes. OJSTA
TLC analysis. For most of the reactions a very small
amount of ailanthinone remained unreacted (~5% - 10%)
as a polar spot and new non-polar compound as major
spot was appeared. The reaction mixture was then diluted
with CH2Cl2 and concentrated under reduced pressure;
the residue was re-dissolved in chloroform (0.2 mL) and
loaded on preparative TLC plate (Silica gel GF, 20 × 20,
500 micron). The preparative TLC purification was per-
formed first by running the plate in 1:3 (EtOAc:hexanes)
and then 1:1 (EtOAc:hexanes). The non-polar UV active
band was collected and desorbed with ethyl acetate (3 ×
2 mL). The combined ethyl acetate layer evaporated un-
der reduced pressure to yield sufficiently pure 1-hydroxyl
modified ailanthinone derivatives (70% - 90%). The pu-
rity of sample was primarily accessed by 1H-NMR ana-
lysis and compared with parent ailanthinone. The newly
derived compounds were submitted without further puri-
fication for their in vitro biological evaluation as anti-
1H-NMR of 1-methyloxycarbonyl- ailanthion e (6)
(CDCl3): δ 0.95 (t, J = 7.5 Hz, 3H, CH3), 0.97 (q, J = 7.8
Hz, 3H , CH 3), 1.09 (brd, J = 6.9 Hz, 3H, CH3), 1.17 (d, J
= 6.0 Hz, 3H, CH3), 1.34 (s, 3H, C10-CH 3) 1.51 (m, 1H),
1.76 (m, 1H), 1.98 (brs, 3H), 2.24-2.39 (m, 2H), 2.42 (q,
J = 6.9 Hz, 1H, CHCO), 2.64 (s, 1H), 3.11 (brd, J = 12.0
Hz, 1H), 3.56 (brs, 1H), 3.68 (d, J = 9.0 Hz, 1H), 3.88 (s,
3H, OCH3), 3.96 (d, J = 9.0 Hz, 1H), 4.63 (dd, J = 1.2,
4.8 Hz, 1H), 5.01 (s, 1H), 5.48 (brd, J = 6.0 Hz, 1H),
5.54 (s, 1H), 6.09 (t, J = 1.8 Hz, 1H, C3-H). LCMS: ob-
served ESI m/z 559 [M+Na]+; calculated for
C27H36O11Na 559.
1H-NMR of 1-ethyloxycarbonyl-ailanth inone (7)
(CDCl3): δ 0.95 (t, J = 7.5 Hz, 3H, CH3), 0.96 (q, J = 7.8
Hz, 3H , CH 3), 1.09 (brd, J = 6.9 Hz, 3H, CH3), 1.17 (d, J
= 6.0 Hz, 3H, CH3), 1.33 (s, 3H, C10-CH3), 1.34 (t, J =
7.5 Hz, CH3) 1.50 (m, 1H), 1.77 (m, 1H), 1.98 (brs, 3H,
CH3), 2.03 (m, 1H), 2.23-2.38 (m, 2H), 2.42 (q, J = 6.0
Hz, 1H), 2.63 (s, 1H), 3.11 (brd, J = 12.0 Hz, 1H), 3.56
(brd, J = 4.5 Hz, 1H), 3.67 (d, J = 9.0 Hz, 1H ), 3.96 (d, J
= 9.0 Hz, 1H), 4.30 (dq, J = 9.0 Hz, 2H, OCH2) 4.62 (dd,
J = 1.2, 4.8 Hz, 1H), 5.00 (s, 1H), 5.48 (brd, J = 9.0 Hz,
1H), 5.60 (brs, 1H), 6.08 (q, J = 1.8 Hz, 1H, C3-H).
LCMS: observed ESI m/z 573 [M+Na]+; calculated for
C28H38O11Na 573.
1H-NMR of 1-isobutyloxycarbonyl-ailanthinone (8)
(CDCl3): δ 0.95 (t, J = 7.5 Hz, 3H, CH3), 0.96 (d, J = 7.5
Hz, 6H, CH3 × 2), 0.96 (q, J = 7.8 Hz, 3H, CH3), 1.09
(brd, J = 6.9 Hz, 3H, CH3), 1.18 (d, J = 6.0 Hz, 3H, CH3),
1.34 (s, 3H, C10-CH3), 1.50 (m, 1H), 1.77 (m, 1H), 1.98
(brs, 3H, CH3), 2.03 (m, 1H), 2.23-2.38 (m, 2H), 2.42 (q,
J = 6.0 Hz, 1H), 2.63 (s, 1H), 3.11 (brd, J = 12.0 Hz, 1H),
3.56 (brd, J = 4.5 Hz, 1H), 3.68 (d, J = 9.0 Hz, 1H), 3.96
(d, J = 9.0 Hz, 1H), 4.03 (dq, J = 9.0 Hz, 2H, OCH2) 4.62
(dd, J = 1.2, 4.8 Hz, 1H), 5.00 (s, 1H), 5.48 (brd, J = 9.0
Hz, 1H), 5.64 (s, 1H), 6.08 (q, J = 1.8 Hz, 1H, C3-H).
LCMS: observed ESI m/z 601 [M+Na]+; calculated for
C30H42O11Na 601.
1-Benzoyl-ailanthione (9) (CDCl3): δ 0.96 (t, J = 7.5
Hz, 3H, CH3), 0.97 (q, J = 7.5 Hz, 3H, CH3), 1.05 (d, J =
6.9 Hz, 3H, CH3), 1.18 (d, J = 6.0 Hz, 3H, CH3), 1.35 (s,
3H, C10-CH3) 1.45 (m, 1H), 1.60 (m, 1H), 1.96 (m, 1H),
1.99 (brs, 3H), 2.80 (dt, J = 1.8, 9.0 Hz, 1H), 2.35 (m,
2H), 2.42 (q, J = 6.9 Hz, 1H, CHCO), 2.70 (s, 1H), 3.21
(brd, J = 12.0 Hz, 1H), 3.38 (t, J = 4.5 Hz, 1H), 3.67 (d, J
= 9.0 Hz, 1H), 3.97 (d, J = 9.0 Hz, 1H), 4.64 (dd, J = 1.2,
4.8 Hz, 1H), 5.42 (s, 1H), 5.45 (brd, J = 6.0 Hz, 1H),
5.55 (s, 1H), 6.10 (q, J = 1.8 Hz, 1H, C3-H), 7.46 (t, J =
Hz, 2H, ArH), 7.61 (t, J = Hz, 1H, ArH), 8.06 (d, J = Hz,
2H, ArH).
1-Piperdinylcarbonyl-ailanthinone (10) (CDCl3): δ 0.96
(t, J = 7.5 Hz, 3H, CH3), 0.98 (q, J = 7.5 Hz, 3H, CH3),
1.11 (brd, J = 6.9 Hz, 3H, CH3), 1.18 (d, J = 6.0 Hz, 3H,
CH3), 1.19 (s, 3H, C10-CH3) 1.53 (m, 1H), 1.77 (m,
1H), 1.96 (m, 1H), 2.01 (brs, 3H), 2.19-2.46 (m, 3H),
2.73 (s, 1H), 2.98 (d, J = 7.8 Hz, 1H), 3.56 (brd, J = 4.5
Hz, 1H), 3.69 (d, J = 9.0 Hz, 1H), 3.96 (d, J = 9.0 Hz,
1H), 4.06 (s, 1H ), 4.63 (dd, J = 1.2, 4.8 Hz, 1H), 5.18 (s,
1H), 5.57 (brd, J = 6.0 Hz, 1H), 6.14 (q, J = 1.8 Hz, 1H,
C3-H). LCMS: observed m/z 590.12, calculated [M+H]+
1-p-Bromophenylsulfonyl-ailanthione (11) (CDCl3): δ
0.96 (t, J = 7.5 Hz, 3H, CH3), 0.97 (q, J = 7.5 Hz, 3H,
CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3), 1.20 (d, J = 6.0 Hz,
3H, CH3), 1.30 (s, 3H, C10-CH3) 1.52 (m, 1H), 1.76 (m,
1H), 1.96 (m, 1H), 1.97 (brs, 3H), 2.25-2.49 (m, 3H),
2.83 (s, 1H), 3.02 (brs, 1H), 3.17 (brd, J = 12.0 Hz, 1H),
3.59 (brs, 1H), 3.69 (d, J = 9.0 Hz, 1H), 3.95 (d, J = 9.0
Hz, 1H), 4.55 (s, 1H) 4.67 (dd, J = 1.2, 4.8 Hz, 1H), 5.10
(s, 1H), 5.48 (brd, J = 6.0 Hz, 1H), 5.99 (q, J = 1.8 Hz,
1H, C3 -H), 7.72 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz,
2H). LCMS: observed ESI m/z 719 and 721 [M+Na]+;
calculated for C31H37BrO11SNa 71 9 a nd 721.
2.3. In Vitro An ti malarial Assay
The antimalarial activities for all new compounds along
with ailanthinone, chloroquine and mefloquine were ob-
tained from three strains of parasites, namely D6 (resis-
tant to mefloquine but susceptible to chloroquine, qui-
nine and pyrimethamine), W2 (resistant to chloroquine,
quinine and pyrimethamine but susceptible to mefloquine)
and TM91C215 (a multiple drug resistant isolate from
Thailand). The assays are based on standard biological
screens performed at WRAIR. The detailed procedure is
described elsewhere [10,11] and is limited to the assess-
ment of the intrinsic activity against plasmodium in the
erythrocyte like asexual life cycle (blood schizontocides).
In brief, the cultured parasites were incub ated with varied
concentration o f diluted drugs in 96 well microtiter plate
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for 48 hrs and then [3H]-hypoxanthine was added and its
uptake in parasite was measured after additional incuba-
tion of 24 h rs by first lysing and recov ering the DNA on
glass fiber filter using Packard Filtermate Cell Harvester.
The data were recorded on scintillation counter (Packard
Top count microplate reader) and the results recorded as
counts per minutes (CPM) per well at each drug concen-
tration divided by the arithmetic mean of the CPM ob-
tained from control untreated parasite wells. The loss in
incorporation of radio-lab eled hypox anthine in parasite is
measure of antimalarial activities of the compound tes-
3. Results and Discussion
Although ailanthinone possess impressive in vitro anti-
malarial activity, further impetus for its development is
hampered by its low natural abundance. In addition, little
information is available about chemical reactivity of ai-
lanthinone, particularly with respect to the hydroxyl
moieties, and their relationship to its observed an timalar-
ial activity. Ogura et al. [12] reported acylation of ailan-
thinone using excess of acetic anhydride/pyridine over-
night to afford the 1, 12, 20-triacetate derivative a he-
miketal ring opened seco-ailanthinone. In another report
glaucarubolone, a parent quassinoid devoid of the C-20
ester, was first protected as the trimethylsilyl ethers and
subsequently esterfied at the C-15 hydroxyl group with
succinic anhydride by Morré et al. [13]. Additionally,
when a controlled acylation reaction of ailanthinone was
performed using acetic anhydride and triethylamine at
low temperature under mild conditio ns, which afforded a
major C-1 acetylated ailanthinone (65%) along with a
minor diacetate (C-1 and C-20) derivative (26%) (Sche-
me 1).
The outcome of the reaction not only indicated that
C-1 hydroxyl group of ailanthinone was the more reac-
tive when compared with the remaining two other hy-
droxyl group at C-12 and C-13 positions, however these
results also suggested that the cyclic hemiketal between
the C-12 ketone and the C-20 hydroxyl was unstable un-
OH Ac2O(2.0eq)/NEt
Minor: 1, 20-diacetate derivative (26%)
Major:1-Acetyl derivative (65%)
Scheme 1. Acetylation of ailanthione with acetic anhydride.
der those reaction conditions. The use of a slight excess
of acetic anhydride may have been responsible for pro-
moting the hemiketal ring to open followed by acetyla-
tion of the resulting C-20 hydroxyl group. Thus, after
few attempts, it was observed that using a more reactive
acylating reagent in less than stoichiometric amount
(~0.95 eq.) in the presence of a tertiary amine base re-
sulted in a highly regioselective 1-hydroxyl acyl-pro-
tected product that could be isolated along with unre-
acted ailanthinone (approximately 5% - 10%). Using
these optimized conditions, several 1-hydroxyl protected
derivatives, such as the ester, carbonate, carbamate and
sulfonate, were synthesized (Scheme 2). It must be noted
here that the exclusive formation of 1-hydroxyl deriva-
tives clearly demonstrates the higher reactivity of the C-1
hydroxyl over the C-12 and C-13 hydroxyl groups. In
addition it can also be inferred from the formation of the
C-1 and C-20 diacetate product that the C-13 hydroxyl
group is the least reactive functional group. This conclu-
sion is borne out by the observation that the hemiacetal
ring opening and subsequent acylation of primary al-
cohol of C-20 hydroxyl. The hemiacetal ring opening is
reversible under the reaction condition but upon ring
opening the C-20-hydroxyl reactivity being primary hy-
droxy group is pretty high thus resulting in formation of
C-20 acylation product. Acylation at C-20 position ren-
der the ring-opening and closing process irreversible and
resist the reformation the cyclic ketal. The new 1-hy-
droxyl protected compounds were primarily character-
ized by 1H-NMR and mass spectral data and compared
the observed data with the parent ailanthinone to confirm
their structures (Figure 1). The derivatives were then
evaluated for their in vitro antimalarial activities with
three available plasmodium strains: D6 (resistant to me-
floquine but susceptible to chloroquine, quinine and
pyrimethamine), W2 (resistant to chloroquine, quinine
and pyrimethamine but susceptible to mefloquine), and
TM91C215 (a multiple drug resistant isolates from Thai-
land). A typical dose response curve is shown in Figure
2 obtained for 1 -ethox ycarbon yl ailan th inone. The r esu lts
of these assays are presented in Table 1. The IC50 values
(ng/mL) obtained from the assays for these compounds
were compared with parent ailanthinone and with two
well established antimalarial drugs, chloroquine and me-
0.95 eq. electrophile
75-90% after Prep TLCO
1-Hydroxy modified ailanthionones
Ailanthi no ne
Scheme 2. Synthesis of 1-Hydroxy modified ailanthinones.
Copyright © 2013 SciRes. OJSTA
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Figure 1. Comparison of NMR spectra of ailanthinone and its 1-OH derivative 8. Chemical shifts in ppm (δ).
Table 1. In vitro antimalarial bioassay data.
IC50 ng/mL
No. Compound D6A W2B TM91C235C
1 Chloroquin 3.5 121.3 34.7
2 Mefloquin 3.3 1.7 15.9
3 Ailanthinone 3.7 5.2 4.4
4 1-Acetyl Ailanthinone 5.3 5.5 8.3
5 1,20-Seco-diacetyl Ailanthinone 37.8 59.4 ND
6 1-Methoxyacetyl Ailanthinone ND ND ND
7 1-Ethoxycarbonyl Ailanthinone 22.3 30.3 ND
8 1-Isobutoxycarbonyl Ailanthinone 9.1 13.9 14.7
9 1-Benzoyl Ailanthinone 16.3 14.7 27.3
10 1-Piperdinylcarbonyl Ailanthinone 1005.8 930.9 1679.9
11 1-P-Bromphenylsulfonyl Ailanthinone 1194.0 1295.4 1780.5
AD6-Chloroquine sensitive mefloquine resistant S i erra Leone strain; BW2-Chlroquine resistance Indo-chine strain ; CTM9 1C2 15 -multidrug r es ista nt stra in.
The analysis of the results from biological assays
clearly demonstrates that the modification of 1-hydroxyl
group alters the antimalarial activities of the compound.
The results from biological data support the notion that
1-hydroxyl group may play role in displaying the ob-
served antimalarial activity and it importance in SAR
studies. All new compounds were shown to possess
comparatively lower antimalarial activity than that of
ailanthinone, however, the smaller the acyl group the
better the retention of observ ed antimalarial activity. The
sulfonyl group carbomoyl group at C-1 position was ob-
served to be deleterious for antimalarial activities for
example compounds 11 and 12 from Table 1. The
hemiketal ring opening between C-12-ketone and C-20
hydroxyl group followed by the functionalization of C-20
hydroxyl group is deleterious to antimalarial activities
Figure 2. Representative dose-response curve (1-ethylcar-
(example 5). This decrease in biological activity may
stem from the loss of rigid cyclic conformation of the
ailanthinone skeleton, but further studies are needed to
confirm these observations. The results presented here
also suggest that proper modification of C-1 hydroxyl
group may improve bioavailability.
In conclusion, the highly selective modification of C-1
hydroxyl group of ailanthinone is possible without pro-
tection/deprotection of the other hydroxyl groups. Such
modification may be accomplished without negatively
impacting antimalarial activity, and thus may be signify-
cant to develop ailanthinone for clinical use in future. In
addition, the cyclic hemiacetal formed between the C-12
ketone and C-20 hydroxyl is likely an essential featu re of
ailanthinone to hold proper conformation of overall
structure that is necessary for its potent antimalarial ac-
4. Acknowledgements
We highly appreciate Dr. Maurice M. Iwu and Dr. Chris
O. Okunji for providing us ailanthinone sample. Thanks
are due to Norma Roncal and Lucia Gerena for collecting
in vitro antimalarial data.
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