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ArtemisoneЧA Highly Active Antimalarial Drug of the Artemisinin Class.

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Antimalarial Drugs
DOI: 10.1002/ange.200503071
Artemisone—A Highly Active Antimalarial Drug
of the Artemisinin Class**
The artemisinins are the most potent and rapidly acting
antimalarial drugs. In response to the global threat of
multidrug-resistant malaria, they are now widely used in
combination therapies with drugs that have a longer half
life.[1] The parent, artemisinin (1), is converted by reduction
Richard K. Haynes,* Burkhard Fugmann, Jrg Stetter,
Karl Rieckmann, Hans-Dietrich Heilmann,
Ho-Wai Chan, Man-Ki Cheung, Wai-Lun Lam,
Ho-Ning Wong, Simon L. Croft, Livia Vivas,
Lauren Rattray, Lindsay Stewart, Wallace Peters,
Brian L. Robinson, Michael D. Edstein,
Barbara Kotecka, Dennis E. Kyle,
Bernhard Beckermann, Michael Gerisch,
Martin Radtke, Gabriele Schmuck, Wolfram Steinke,
Ute Wollborn, Karl Schmeer, and Axel Rmer
[*] Prof. Dr. R. K. Haynes, Dr. H.-W. Chan, Dr. M.-K. Cheung,
Dr. W.-L. Lam, Dr. H.-N. Wong
Department of Chemistry
Open Laboratory of Chemical Biology
Institute of Molecular Technology for Drug Discovery and Synthesis
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong (P.R. China)
Fax: (+ 852) 2358-1594
E-mail: haynes@ust.hk
Dr. B. Fugmann
Bayer Innovation GmbH (Germany)
Prof. Dr. J. Stetter
Bayer AG Central Research (Germany)
Prof. Dr. K. Rieckmann, Dr. M. D. Edstein, Dr. B. Kotecka,
Dr. D. E. Kyle[+]
Army Malaria Institute (AMI)
Enoggera, Queensland 4052 (Australia)
Prof. Dr. H.-D. Heilmann, Dr. B. Beckermann, Dr. M. Gerisch,
Dr. M. Radtke, Dr. G. Schmuck, Dr. W. Steinke
Bayer HealthCare (Germany)
Dr. S. L. Croft, Dr. L. Vivas, Dr. L. Rattray, Dr. L. Stewart
London School of Hygiene and Tropical Medicine (UK)
Prof. Dr. W. Peters, B. L. Robinson
Northwick Park Institute for Medical Research, Harrow (UK)
Dr. U. Wollborn
Bayer MaterialScience AG (Germany)
Dr. K. Schmeer
Bayer CropScience AG (Germany)
Dr. A. RDmer
Analytik und Metabolismusforschung Service GmbH (Germany)
[+] Current affiliation:
Walter Reed Army Institute of Research (USA)
[**] Work at the HKUST was funded by Bayer AG Central Research,
Leverkusen, the Institute of Molecular Technology for Drug
Discovery and Synthesis through the HKSAR University Grants
Committee Areas of Excellence Fund, and the HKSAR Research
Grants Council through the Competitive Earmarked Research
Grants Scheme. The Medicines for Malaria Venture (MMV),
Geneva, also provided financial support of the work at Bayer, and
through Bayer at HKUST and other centers. Dr. W. Collins (Centers
for Disease Control, Atlanta) supplied P. falciparum FVO strain used
for the primate studies.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2136
into dihydroartemisinin (DHA, 2)[2] and then into the hemiester artesunate (ATS, 3; 65 % yield from DHA).[3] Artemether (4)[4] and arteether (5)[5] are obtained from DHA,
methanol, and an acid catalyst in about 60 % yield after
fractional crystallization to remove the a-epimers. Therefore,
the most accessible derivative is ATS (3). Although artemisinins display variable pharmacokinetics and low bioavailability,[6] such properties are countered by selective uptake into
parasitized erythrocytes.[7] Their induction of phase I
enzymes, primarily CYP3A4 and CYP2B6, leads to a timedependent decrease in efficacy.[8] Additionally, metabolism of
artesunate and the ethers to DHA (2) is facile.[8, 9] The
artemisinins, especially DHA, are neurotoxic according to in
vivo assays with animal models[10] and in vitro studies with
neuronal cell cultures.[11–13] Although neurotoxicity is dependent upon the route of administration in animal screens,[14] it
has not yet been definitively established to be a problem in
humans.[15] From a regulatory viewpoint, however, it is a
contentious issue, and the development of new artemisinin
therapies must be conducted with this in mind.
Despite an immense effort, no new artemisinin derivative
has reached development status. 10-Alkylaminoartemisinins
6 (R’ = H, alkyl; R’’ = alkyl; R’,R’’ = cycloalkyl) are an
artemisinin class whose preparation entails chemistry distinct
to that leading to other derivatives and which extends the
efficacy limit beyond those of the known artemisinins.[16, 17]
For any such compound to be developed into a new drug, the
production cost must be comparable to that of ATS (3),[18]
unless a greater efficacy is obtained when a commensurate
increase in cost is permitted. As the interaction of artemisinins with their likely target, the PfATP6 Ca2+ pump, is still
unclear,[19, 20] a “rational design” approach is not possible and
emphasis must be placed on improving systemic behavior.
Whilst this depends upon a number of factors,[21] an enhancement of aqueous solubility to a limiting value and attenuation
of lipophilicity as assessed through the log P parameter (P is
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2006, 118, 2136 –2142
Angewandte
Chemie
the octanol–water partition coefficient) are beneficial.[22, 23] One report in the artemisinin area
addresses the lipophilicity issue, wherein enzymatic
hydroxylation of the lipophilic arteether (log P =
3.89–3.99) provides products with log P values of
2.6–2.7, considered to be in an optimal range for
systemic activity.[24] However, the corollary that
lipophilic artemisinins are neurotoxic[25, 26] adds substantial impetus to the drive to attenuate lipophilicity. As neurotoxicity is likely to be associated with a
specific target,[11, 27] a linear correlation between
neurotoxicity and lipophilicity for a compound
series is unlikely.[25] However, it is clear that in
order to depress neurotoxicity, log P must be reduced
and, at the same time, phase I metabolism to DHA
must be blocked. As the alkylaminoartemisinins 6
will not undergo such metabolism, polar groups inert
to phase I and phase II metabolism[26] are best
incorporated into the 10-alkylamino substituent
itself. However, the use of hydroxy, carboxy, or
primary amino groups capable of forming phase II
conjugates is proscribed.
The amines 9–11[16, 28, 29] and 12–16[30] (40–60 %)
were obtained from DHA a-trimethylsilyl ether 7
Scheme 1. Preparation of 10-alkylamino derivatives 9–16; compound 13 is obtained by
and trimethylsilyl bromide (TMSBr), followed by
oxidation of 12; compound 14 is obtained by either treatment of 8 with thiomorpholinetreatment of the intermediate bromide 8 formed in
S,S-dioxide or oxidation of 12, which itself is obtained from 8 and thiomorpholine.[16, 29, 30]
situ with the amine nucleophile (Scheme 1, route a).
Compounds 17 and 18 were prepared according to published procedures.[28]
Oxidation of the sulfide 12 also provided sulfoxide 13
mCPBA = m-chloroperbenzoic acid; NMO = N-methylmorpholine-N-oxide;
TPAP = tetra-n-propylammonium perruthenate.
or sulfone 14. A more straightforward route involved
treatment of DHA first with a mixture of NaBr and
TMSCl in toluene and then with the amine
(Scheme 1, route b). Under these condition, DHA is conaqueous solubility. Compound 14, which is highly crystalline
verted by the TMSBr formed in situ into the TMS ether 7, and
and easily purified, displays aqueous solubility that exceeds
then into the bromide 8, whose presence was detected by
the limiting requirements for a drug.[22] Compounds 13 and 15
1
[28]
are more soluble but are more costly to prepare than 14.
H NMR spectroscopy.
For most compounds, products
Although compound 16 has a low calculated log P value, it
from multigram- or multikilogram-scale reactions (comalso has a low aqueous solubility.
pounds 12 and 14) were isolated by crystallization of the
Neurotoxicity was assessed with the in vitro model
crude product mixtures. Thus, the candidate compounds are
developed for screening compounds required for medicinal
relatively accessible and are produced as isomerically pure,
and other purposes.[32] As artemisinins exert their neuroair-stable substances.
Assessment of physicochemical properties, neurotoxicity,
toxicity by acting selectively on brain stem cells,[11–13, 27, 33]
and efficacy against malaria was next carried out. For
primary neuronal brain stem cell cultures from fetal rats,
comparative purposes, the lipophilic 4-fluorophenyl and 4with endpoints of cytotoxicity and neurofilament integrity,
chlorophenyl derivatives 17 and 18 were also studied.[16, 28]
were used. Intracellular ATP levels, which are a sensitive and
early marker of cytotoxicity,[27, 33] were also measured
Measured and calculated[31] log P values (Table 1) reveal that
artemether 4 is relatively lipophilic. Because DHA (2) exists
(Table 2). With a “no observable effect concentration”
as two epimers in solution, log P appears as two values, 2.35
(NOEC) on neurofilaments of less than 0.001 mg mL 1,
and 2.73; the solubility of 2 could not be measured because of
DHA displayed the greatest neurotoxicity. The neurotoxicity
decomposition. Compounds 9, 10, and 12, and especially 17
of 9–11 contrasts with the nontoxicity of 14. NOEC and IC50
and 18, are lipophilic with high log P values and very low
values for cytotoxicity with cortical neurons were generally
Table 1: Aqueous solubility and octanol–water partition coefficients.
1 [a]
Solubility [mg L ]
log P[b]
log P (calcd)[d]
1
3
4
9
10
11
12
13
14
15
16
17
18
63
2.94
3.15
565
2.77
3.04
117
3.98
3.51
8
5.62
5.15
<2
4.78
4.07
28.4
3.05
3.26
<2
4.97
3.98
1251
2.63
2.03
89
2.49
2.08
294
3.36
2.29
10
[c]
2.30
<1
5.59
5.18
<1
6.15
5.58
[a] Aqueous solubility at pH 7.2. [b] Octanol–water partition coefficient for the neutral compound determined at pH 7.4, except that for artesunate (3)
which was determined at pH 2 by HPLC. [c] Not determined. [d] Calculated log P value.[31]
Angew. Chem. 2006, 118, 2136 –2142
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2137
Zuschriften
Table 2: Effects of the test compounds on viability and neurofilaments in rat primary neuronal brain
stem cell cultures.[a]
Compound
Viability [mg mL 1][b]
NOEC[e]
IC50
ATP [mg mL 1][c]
NOEC[e]
IC50
Neurofilaments [mg mL 1][d]
NOEC[e]
IC50
1
2
3
4
9
10
11
12
14
15
17
18
1.0
0.1
0.1
1.0
0.1
0.01
0.1
1.0
> 10
10
1.0
1.0
0.01
0.01
–
–
–
–
< 0.001
1.0
> 10
1
1
0.01
0.001
< 0.001
0.1
0.01
10
0.1
0.001
0.001
> 10
0.001
0.001
0.001
> 10
5.0
> 10
> 10
> 10
10
4.5
> 10
> 10
> 10
> 10
> 10
0.08
0.08
–
–
–
–
< 0.001
8.5
> 10
6.3
6.3
0.08
0.05
0.01
5.0
0.1
> 10
3
0.04
> 10
> 10
> 10
> 10
0.05
[a] Determined on fetal rat brain stem cells (E18–E19) cultured to generate a permanent neuronal
network during days 1–8; compounds in dimethyl sulfoxide (DMSO) were applied at 0.001, 0.01, 0.1, 1,
and 10 mg mL 1 for 7 days starting on day 9. [b] Cytotoxicity was measured by viability based on the
activity of neuron-specific enolases. [c] ATP (adenosine triphosphate) levels measured at 1 day after
initial administration.[27, 33, 35] [d] Neurotoxicity was assessed by the effect on the cytoskeleton on day 7.
[e] No observable effect concentration.
between in vivo and in vitro neurotoxicity
has already been noted with artemisinins 1–
4.[11, 13, 27, 33]
Antimalarial IC50 values from in vitro
screens of the 10-alkylamino compounds 9–
18 against Plasmodium falciparum chloroquine (CQ)-sensitive D6 or 3D7 and CQresistant W2 or K1 strains generally were
substantially lower (to over 20-fold for
compounds 9 and 10) than those of ATS
(3). The compounds also display superior
activities in in vivo screens in the four-day
PetersG model[36] against CQ-sensitive
P. berghei and CQ-resistant P. yoelii in
mice (Table 3). Compounds 9–12 were
exceedingly active but are excluded from
further consideration because of toxicity,
and unfavorable physicochemical properties. Overall, compound 14 (artemisone)
emerges as the development candidate.
greater than 10 mg mL 1, even for
Table 3: In vivo screens against CQ-sensitive P. berghei N strain and CQ-resistant P. yoelii NS strain.[a]
the highly neurotoxic 11. However,
P. berghei
P. yoelii
Compound
P. berghei
P. yoelii
DHA is also cytotoxic towards
artesunate index[b]
artesunate index[b]
ED90 [mg kg 1]
ED90 [mg kg 1]
cortical neurons (NOEC(DHA) =
sc
po
sc
po
sc
po
sc
1 mg mL 1,
NOEC(artemisinin)
3
7.2
7.1
1.0
1.0
22.0
–
1.0
> 50 mg mL 1) and non-neuronal
9
0.8
3.5
9.0
2.0
0.85
3.0
25.9
cell lines (NOEC(liver HEP-G2,
10
0.6
2.8
12
2.5
0.52
2.0
42.3
epithelium liver IAR, kidney LLC14
1.5
3.1
4.8
2.3
3.9
5.0
5.6
PK1) = 0.1 mg mL 1, NOEC(arte17
1.16
5.0
6.2
1.4
1.08
–
20.4
18
3.8
4.6
1.9
1.7
3.0
–
7.3
misinin) > 10 mg mL 1).[27, 32, 33] In
general, the lipophilic compounds
3
4.6
9.3
1.0
1.0
42.0
–
1.0
are neurotoxic. Neurotoxicity of
11
0.18
1.3
25.6
7.15
1.25
1.84
33.6
the polar ATS (3) is likely due to
12
0.51
1.9
9.0
4.9
0.61
2.0
81.0
facile hydrolysis in situ to DHA.
As the relatively polar DHA and
3
12.0
–
1.0
–
50.0
–
1.0
13
9.0
–
1.3
–
10.0
–
5.0
artemisinin may undergo ring[36]
opening under aqueous conditions
[a] Peters’ four-day test with mice treated daily subcutaneously (sc) or orally (po) from the day of
to provide rather different strucinfection (day 0) through to day 3; results (ED90 values) are evaluated from parasite counts in peripheral
tures,[7, 34] the actual nature of the
blood on day 4. [b] ED90(artesunate)/ED90(compound).
neurotoxic agent is uncertain.
Compound 11 is anomalous in
Even though it is not the most active candidate, its lack of
that it also elicits acute systemic toxicity in an in vivo
toxicity couples well with its accessibility and tractable
screen. The outcome of pilot tolerability studies in animal
physicochemical properties. It was therefore subjected to
models, which employ standard indicators of neurotoxic
more-detailed screening in conjunction with the comparator
effects,[35] reflects the results of the in vitro studies. Oral
drug, ATS (3), the most accessible of the current artemisiadministration via gavage in corn or sesame oil of ATS (3) at
nins.[1, 9]
10 and 50 mg kg 1 day 1 for 14 days to female rats induces
uncoordinated gait and vocalization from days 7–11 at the
In comparative screens in vitro against a panel of multihigher dose. Compounds 10 at the higher dose and 11 at the
drug-resistant isolates of P. falciparum, artemisone (14) is
lower dose are fatally toxic from days 2–4, generating prior
significantly more active than ATS, CQ, and pyrimethamine,
symptoms of acute systemic toxicity. At 50 mg kg 1 day 1,
irrespective of the resistance profile (Figure 1). Ex vivo
bioassay represents an effective method for assessing both
substantial body-weight loss, coupled with reduced motility,
comparative bioavailability and efficacy of an orally adminuncoordinated gait, and piloerection are observed with
istered drug.[38] Oral administration of a 30 mg kg 1 single
compounds 9, 12, 17, and 18. Compound 16 induces uncoordinated gait from day 1, with a slight decrease in body weight.
dose of artemisone (14) or ATS (3) to healthy Saimiri
In contrast, no effects are detectable with compounds 13–15;
monkeys and assay of plasma amples drawn from the
the weight gains are no different to controls. The parallel
monkeys against P. falciparum K1 strikingly reveal that
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Angew. Chem. 2006, 118, 2136 –2142
Angewandte
Chemie
tended to have later recrudescences
than monkeys in the ATS group.
Complete cure was achieved in
infected monkeys receiving a
single oral dose of artemisone
(10 mg kg 1)
plus
mefloquine
(MFQ, 5 mg kg 1), although recrudescence occurred with a lower
MFQ dose (2.5 mg kg 1). Cure was
also achieved with oral artemisone
(10 mg kg 1 day 1) plus amodiaquine (AQ, 20 mg kg 1 d 1) given
for 3 days. Therefore, in vivo efficacy is fully demonstrated. As the
problem of recrudescence is
common to all artemisinins, artemisone will best be used in conjunction with a longer half-life drug
Figure 1. In vitro antimalarial activities for artemisone, artesunate, chloroquine (CQ), and pyrimethamine (PYR) against both drug-sensitive (3D7) P. falciparum and to isolates that are variously
such as MFQ or AQ; this will
resistant (R) to CQ, PYR, and mefloquine (MFQ), assayed by administration of the compounds in
additionally protect each drug partDMSO to parasites incubated with 3H-hypoxanthine. Inhibition of the uptake of hypoxanthine is
ner against the emergence of resis1 [37]
expressed as the concentration at 50 % inhibition (IC50) in ng mL . 3D7 (clone of NF54 isolate,
tance.[1, 9, 18]
Netherlands); K1 (Thailand) CQ-R, PYR-R; VS1 (Vietnam) CQ-R, PYR-R; 7G8 (Brazil) CQ-R, PYR-R;
To demonstrate the lack of
HB3-B2 (Honduras) PYR-R; FCB (Colombia) CQ-R; FCR3 (Gambia) CQ-R, PYR-R; Tm90 C2A
metabolism
to DHA and to identify
(Thailand) CQ-R, PYR-R, MFQ-R; W2 (Indochina) CQ-R, PYR-R; FCR-8 (Gambia); FCC2 (Hainan);
metabolites formed in vitro and in
DD2 (clone from W2) CQ-R, PYR-R. Error bars represent the standard deviation about the arithmetic
mean.
vivo, labeled artemisone 14* incorporating either 14C or 2H in the
metabolically
inert
15-methyl
group was required. The exocyclic methylidene was cleaved
artemisone has a greatly enhanced bioavailability, as reflected
from artemisitene (19)[39] to give the known[40] dicarbonyl
in the greater and significantly more sustained activity in
plasma compared to ATS (Figure 2). Next, aotus monkeys
compound 16, treatment of which with 2H- or 14C-methyliinfected with P. falciparum FVO isolate, which is resistant to
dene triphenylphosphorane provided labeled artemisitene
CQ and antifolates, were treated with each of ATS and
19*, as shown in Scheme 2 for the deuteriated reagents. As
artemisone at 10 mg kg 1 day 1 for 3 days. The artemisoneattempted reduction of the exocyclic methylidene with
conjugate hydride donors failed, the carbonyl group in 19*
treated group cleared parasites within 24 h after commencewas first reduced and the resulting allylic alcohol 21* was
ment of treatment, whereas parasites were still present 48 h
reduced with either Et3SiH for the 14C-labeled compound or
after treatment with ATS (Table 4). One monkey (no. 7,
Table 4) in the artemisone group was cured, and the others
Et3Si2H for the 2H-labeled compound to give glycal 22*. The
latter was converted into 12* by stereoselective addition of HCl and treatment of
the intermediate 10b-chloride with thiomorpholine to give labeled 12*; oxidation
provided labeled artemisone 14*. This is
the first semisynthesis of an artemisinin
bearing a labeled group at a metabolically
inert region of the artemisinin skeleton, for
which total, albeit elegant, syntheses were
previously used.[41]
In vitro incubation of 14* with human
liver microsomes gave after 30 min metabolites M1
( 34 % of total radioactivity (TRA)), M2
( 19 % of TRA), M3 ( 16 % of TRA),
and smaller amounts of M4 and M5 (each
< 6 % TRA) at approximately 77 % conFigure 2. Ex vivo maximum inhibitory dilutions (MID) of plasma samples obtained from
version of 14* (Scheme 2). Each metabolite
healthy Saimiri monkeys at 1–4 and 6 h after a single oral dose of artemisone (14) or
was isolated and identified unambiguously
artesunate (3; 10 mg kg 1 each) required to inhibit maturation of 90 % P. falciparum K1
by the use of 1D and 2D NMR spectrofrom rings to schizonts. Error bars represent the standard error of the mean of MID data
scopic analyses coupled with high-resoluobtained for four monkeys with each drug.
Angew. Chem. 2006, 118, 2136 –2142
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2139
Zuschriften
human liver microsomes and 14 recombinant CYP isoforms together with selective
inhibitors indicated that only recombinant
Monkey
Initial parasitaemia
Time to
Compound
Parasitaemia [ M 103 mL 1]
[M103 mL 1]
on day n[b]
recrudescence
[10 mg kg 1 day 1]
CYP3A4 metabolizes artemisone in signifidays 0–2
day 1
day 2
day 3
[days]
cant amounts, with trolleandomycin, azamulin, and ketoconazole being efficient
1
145
3
2.1
0.2
0
9
inhibitors. Treatment of human hepatocytes
2
515
3
15
0.6
0
20
3
340
3
40
0.4
0
18
with 4–10 000 ng L 1 of artemisone had a
4
490
14
0
0
0
20
borderline inductive effect on CYP2B6 and
5
10
14
0
0
0
20
CYP3A4 at the highest concentration, with
6
150
14
0
0
0
29
no induction of CYP1A2 and CYP2C19.
7
85
14
0
0
0
–
Incubation of artemisone and standard
[a] Two aotus monkeys were infected with blood containing aotus-adapted P. falciparum FVO isolate
substrates
with
CYP1A2,
-2A6,
resistant to CQ and antifolates. Blood was drawn from the infected monkeys and used to infect five
-2C9, -2C19, -2D6, -2E1, and -3A4 has no
malaria-naNve monkeys. 6–9 Days after inoculation, ATS (3) and artemisone (14) were administered
effect on substrate metabolism. Therefore,
orally for 3 days at 10 mg kg 1 day 1 (total 30 mg kg 1). Thick blood films were examined microscopically
induction of CYP3A4 or CYP2B6 with
twice a week; these were considered to be negative when no parasites were detected after examination of
artemisone, in contrast to the current arte100 microscopic fields ( 0.1 mL blood). [b] Parasitaemia on days after the initial treatment on day 0.
misinins, will likely not be a problem
in clinical use.[43]
All aspects of preclinical screening, including the results of pharmacokinetic studies and a detailed toxicological assessment, allow artemisone to be carried forward into
clinical trials. We have shown that
artemisinins which are structurally
distinct to but significantly more
active than current artemisinins can
be prepared through embedding
metabolically inert polar groups
within the alkylamino substituents
attached directly to C10 of the artemisinin nucleus. The development
candidate chosen from within this
class, artemisone, has a different
metabolic profile to the current artemisinins and displays favorable phys14
2
Scheme 2. Preparation of labeled artemisone 14* (C*H3 = CH3 or C H3) and CYP3A4-mediated formation of
icochemical properties and negligimetabolites M1–M5 (Ph3P=14CH2, Et3SiH for 14C label; Ph3P=C2H2, Et3Si2H for 2H label; yields quoted for
ble neuro- and cytotoxicities. Notaisolated deuteriated compounds). Reagents and conditions: a) NaIO4/RuCl3, CCl4, MeCN, 20 8C, 54 %;
2
bly, in key with the enhanced antib) C H3PPh3Br, n-C4H9Li, N2, THF, 78 8C; then 20, 78–20 8C, 20 h, 48 %; c) iBu2AlH, CH2Cl2, 78 8C, 2 h,
malarial activity of artemisone,
> 98 %; d) Et3SiH or Et3Si2H, TFA, 78 8C, 4 h, 40 %; e) HCl, CH2Cl2, 0 8C; then thiomorpholine, Et3N, 0 8C,
inhibition of the likely target, the
45 min; 50 % to 12*; then mCPBA, K2CO3, Et2O, 0 8C, to 14*, 72 %. TFA = trifluoroacetic acid.
parasite Ca2+ pump PfATP6,[19] is
much greater for artemisone than
artemisinin: Ki values for artemisinin and artemisone are
tion mass spectrometry. The identity of M1 was also verified
by independent preparation of unlabeled M1 from artemi169 31 and 1.7 0.6 nm, respectively, and for the P. vivax
sone and ozone, according to a method used to desaturate
orthologue, the Ki values are 7.7 4.9 and 0.072 0.012 nm,
tertiary amines.[42] Rat and dog microsomes produce M1 with
respectively.[20] The cost of artemisone, which is obtained in 2–
larger amounts of M2 and M3, and a large amount of M1 with
3 steps from artemisinin, is compatible with the requirement
a small amount of M3, respectively. Incubation with human,
for an antimalarial drug, and its enhanced activity over the
dog, and rat hepatocytes largely reflect the metabolism with
current artemisinins will permit the use of lower clinical dose
the microsomes. DHA could not be detected in any of the
regimens, thereby augmenting the supply of artemisinin.
systems. Plasma from rats administered orally with artemiIronically, the current supply shortfall[44] is largely due to the
sone contains M2 and M3 and minor amounts of M1, M4, and
demand for the fixed combination drug artemether–lumifanM5. As the in vivo plasma profile of metabolites of rats
trine, of which that amount of drug containing half a gram of
resembles the in vitro profiles from rat liver microsomes and
artemether is required to cure a malaria patient.[45] In 2005,
hepatocytes, the metabolism of artemisone in humans will
the estimated global demand was for 120 million adult
likely reflect formation of M1–M5 in human microsomes and
treatment courses.[46] Thus, approximately 114 tons of arte14
hepatocytes. Incubation of C-labeled artemisone with
misinin is required, given that the overall chemical yield of
Table 4: In vivo activities of artesunate 3 and artemisone 14 against P. falciparum FVO in aotus
monkeys.[a]
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Angewandte
Chemie
artemether from artemisinin is 53 %. The time to move on to
new, more-active artemisinins is at hand.
Received: August 29, 2005
Revised: November 4, 2005
Published online: January 30, 2006
.
Keywords: antimalarial agents · artemisinins ·
medicinal chemistry · metabolism · neurotoxicity
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Zuschriften
P. falciparum K1 in vitro. Metabolite M1 (IC50 = 1.7 ng mL 1)
and M3 (IC50 = 2.3 ng mL 1) reveal similar activities to that of
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