Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p- substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric acids

Article abstract of DOI:10.1021/jm9607919

To search for water soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric acids were synthesized as new potential antimalarial agents. Two approaches were taken in the design of these new molecules in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. The new compounds showed a 2-10-fold increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the corresponding S-diastereomers. p-Chlorophenyl and p-bromophenyl derivatives showed in vivo oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid (1/8 cured), whereas p-fluorophenyl and p- methoxyphenyl analogs demonstrated activity only comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a day). The in vivo antimalarial activity of these new compounds correlates with their SD50 (50% parasitemia suppression dose). The biological results suggested that an electronic effect, besides the lipophylicity, may play a role in determining the efficacy of this class of compounds.

Full text of DOI:10.1021/jm9607919

1396
J . Med. Chem. 1997, 40, 1396-1400
An tim a la r ia l Activity of New Dih yd r oa r tem isin in Der iva tives. 7.
4-(p-Su bstitu ted p h en yl)-4(R or S)-[10(r or â)-d ih yd r oa r tem isin in oxy]bu tyr ic
Acid s1-6
Ai J . Lin,* Akram B. Zikry, and Dennis E. Kyle
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100
Received November 12, 1996X
To search for water soluble dihydroartemisinin derivatives with higher efficacy and longer
plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted
phenyl)-4(R or S)-[10(R or â)-dihydroartemisininoxy]butyric acids were synthesized as new
potential antimalarial agents. Two approaches were taken in the design of these new molecules
in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of
oxidative dealkylation of the target compounds. The new compounds showed a 2-10-fold
increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum
than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the
corresponding S-diastereomers. p-Chlorophenyl and p-bromophenyl derivatives showed in vivo
oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid
(1/8 cured), whereas p-fluorophenyl and p-methoxyphenyl analogs demonstrated activity only
comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a
day). The in vivo antimalarial activity of these new compounds correlates with their SD50
(50% parasitemia suppression dose). The biological results suggested that an electronic effect,
besides the lipophylicity, may play a role in determining the efficacy of this class of compounds.
Ba ck gr ou n d
The effectiveness of artemisinin (1a ) and its deriva-
tives as antimalarial drugs for the treatment of multi-
drug resistant Plasmodium falciparum has received
increasing attention in recent years.7-11 Due to the
increasing prevalence of multidrug resistant P. falci-
parum, several artemisinin derivatives are being used
increasingly in areas such as Southeast Asia.11b The
practical values of these novel malarial therapeutic
agents, nevertheless, are impaired by their (a) poor
solubility in either oil or water,8a (b) high rate of parasite
recrudescence after treatment,8b (c) short plasma half-
life,12,13 and/or (d) poor oral activity (active only at very
high dosage).8b Chemical modifications of artemisinin
has resulted in a number of analogs with improved
efficacy and increased solubility in either oil, i.e.,
arteether and artemether8a,14 (1b and 1c), or water, i.e.,
much longer plasma half-life (1.5-3 h) than oil soluble
sodium artelinate15 (1d ) and sodium artesunate16 (1e).
analogs.17 It is highly effective when administered
Both artemether and arteether are more potent than
artemisinin but have a short plasma half-life and
orally against P. berghei20 and produced complete cures
against P. knowlesi infection in rhesus monkeys at 15
produce fatal CNS toxicity in chronically dosed rats and
mg/kg × 3 days.21 Furthermore, recent CNS toxicity
dogs.17,18 Likewise, the usefulness of sodium artesunate
studies indicated that the water soluble dihydroarte-
in the treatment of cerebral malaria and multidrug
misinin derivatives such as artesunate and artelinate
possess substantially less CNS toxicity in rats and dogs
resistant P. falciparum is offset by problems associated
with its instability in aqueous solution,1 the high rate
than oil soluble analogs such as artemether and arte-
of recrudescence, and the extremely short plasma half-
ether.18
life (20-30 min).17a Analogs with molecular modifica-
Pharmacokinetic data of arteether, artemether, and
tions other than the 10-position of artemisinin or the
artesunic acid demonstrated a rapid enzymatic conver-
simpler analogs of artemisinin were reported by several
sion of these compounds to dihydroartemisinin (DQHS)
laboratories in recent years.19 Some of the newly
in vivo or in liver homogenate.17 The high rate of
recrudescence and the low rate of radical cure of
dihydroartemisinin derivatives in general may be re-
reported agents showed better in vitro antimalarial
activities than aforementioned drugs of this class.
Sodium artelinate was designed to overcome the
lability of sodium artesunate in aqueous solution. It is
not only very stable in aqueous solution1 but also has
lated to the short plasma half-life of the compounds, and
the short plasma half-life, in turn, may be a result of
fast conversion of DQHS derivatives to DQHS. The
slower rate of dealkylation of artelinic acid to DQHS
than artemether or arteether may account for the longer
X Abstract published in Advance ACS Abstracts, March 15, 1997.
S0022-2623(96)00791-1 This article not subject to U.S. Copyright. Published 1997 by the American Chemical Society

Notes
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9 1397
Sch em e 1
plasma half-life of the former than the latter lipophilic
compounds. A feasible approach to prolong the plasma
half-life of this class of compounds, therefore, was to
fabricate new analogs that are poor substrates for
cytochrome P-450, an enzyme which catalyzes the
oxidative hydroxylation of drugs in vivo. Theoretically,
the substrate property (hydroxylation potential at the
R-methylene carbon of artelinate) of the compounds can
be altered by manipulating the electron density of the
aromatic ring of artelinic acid or by exerting steric
hindrance to the R-methylene carbon.6 As part of an
ongoing research project in search for stable, water
soluble, high potency, long-acting, and orally active
antimalarial drugs with minimum CNS toxicity, a series
of diastereomers of 4-(p-substituted phenyl)-4(R or S)-
[10(R or â)-dihydroartemisininoxy]butyric acids, based
on the above mentioned rationale, were synthesized.
The in vitro antimalarial activities of the new com-
pounds were assessed against two clones (D-6 and W-2)
of P. falciparum, and the in vivo activities of four water
soluble final target compounds were determined in mice
infected with P. berghei (KBG-173).
products. The relationship between coupling constant
and the configuration at C10-position was discussed in
previous papers of this series.1,2 An oxonium ion 3 was
proposed to be involved in the ether formation.1,2
Likewise, the condensation reaction between dihydro-
artemisinin (2) and the racemic mixture of the methyl
4-(p-substituted phenyl)-4-hydroxybutyrates (4) gave
predominantly the â-isomers which consisted of equal
amount of R- and S-diastereomers, except the methoxy
analog whose product mixture contained mainly â(R)-
isomer. No pure â(S)-isomer of methoxy analog [5â(S),
R ) OMe] was isolated. The R-isomers of 5 formed fine
crystals, but the S-isomers were generally low melting
or gum. The differences in physical properties between
R- and S-isomers render a higher isolated yield of the
former than the latter.
Ether formation on reaction of dihydroartemisinin (2)
with alcohols 4 yielded products 5 which added two new
chiral centers. Therefore, a total of four stereoisomers
in each product mixture is possible. Since preponderant
condensation products are â-isomers, both â(R) and â(S)
of fluoro, chloro, and bromo analogs were isolated and
characterized. However, only one â(R)-isomer of meth-
oxy analog was isolated; the corresponding â(S)-isomer
was detected by NMR to be a minor component of the
isomeric mixture. A small quantity of the pure R(R)-
isomer of methoxy and chloro analogs were also ob-
tained.
Ch em istr y
Dihydroartemisinin (2) was prepared by sodium boro-
hydride reduction of artemisinin as previously re-
ported.1,2 The new ether derivatives of dihydroarte-
misinin were prepared by treatment of 2 with an
appropriate alcohol 4 in the presence of boron trifluoride
etherate at room temperature (Scheme 1). The yield of
the purified condensation products 5 ranged from 40 to
75% (Table 1). The purification was achieved by the
use of a silica gel chromatotron, preparative TLC, or
column chromatography. In previous work related to
this study,6 the condensation between dihydroartemisi-
nin and benzylic alcohols gave the â-isomers, which
have small coupling constants (J ) 3.5 Hz) between
C9-H and C10-H, as the major condensation products.
The R-isomers, which have a larger coupling constant
(J ) 9-10 Hz) between C9-H and C10-H than the
â-isomers, were less than 5% of the condensation
The starting alcohols (4) were prepared by esterifi-
cation of the corresponding keto acids in boiling absolute
methanol in the presence of boron trifluoride etherate.
Sodium borohydride reduction of the keto esters gave
the racemic alcohols 4.
Although the resolution of a racemic mixture to its
single R- and S-isomers is difficult and tedious, the
multi-asymmetric carbon centers of the dihydroarte-
misinin moiety of the new analogs serve as an excellent
internal resolving agent for separation of the diastereo-
meric derivatives. The dihydroartemisinin moiety,
therefore, renders the new diastereomeric derivatives
dissimilar in their physical properties such as melting

1398 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9
Ta ble 1. Physical Properties of Dihydroartemisinin Derivatives
Notes
1H-NMR (ppm)
C12-H (s)
compd
R1
Cl
Cl
Cl
F
F
Br
Br
R2
*(#)
formula
mp (°C) yield (%)
C10-H (d)
C4′-H
analysis
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6d
6e
6f
Me S(â)
Me R(â)
Me R(R)
Me R(â)
Me S(â)
Me R(â)
Me S(â)
C26H35O7Cl
gum
118
148
128
gum
123
gum
131
124.6
gum
147
108
gum
145
gum
70
30
40
5
43
30
55
20
45
7
85
75
70
85
70
75
70
5.01 (J ) 3.5 Hz)
4.59 (J ) 3.6 Hz)
4.21 (J ) 9 Hz)
4.59 (J ) 3.5 Hz)
5.01 (J ) 3.5 Hz)
4.60 (J ) 3.4 Hz)
5.00 (J ) 3.3 Hz)
4.62 (J ) 3.5 Hz)
4.23 (J ) 9 Hz)
5.03 (J ) 3.4 Hz)
4.61 (J ) 3.6 Hz)
4.61 (J ) 3.4Hz)
5.04 (J ) 3.4 Hz)
4.60 (J ) 3.5 Hz)
5.03 (J ) 3.2 Hz)
4.63 (J ) 3.5 Hz)
4.95
5.47
5.19
5.48
4.90
5.47
4.95
5.49
5.18
4.94
5.48
5.49
4.89
5.48
4.95
5.50
4.77 (t, J ) 5.8 Hz)
4.83 (t, J ) 6.8 Hz)
4.89 (d,d J ) 5.5, 9 Hz)
4.82 (t, J ) 6.6 Hz)
4.74 (t, J ) 6 Hz)
C,H
C,H,Cl
N/A
C,H
C,H
C,H,Br
C,H,Br
C,H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
26H35O7Cl
26H35O7Cl
26H35O7F
26H35O7F
26H35O7Br
26H35O7Br
27H38O8
4.81 (t, J ) 7 Hz)
4.75 (t, J ) 5.9 Hz)
4.77 (t, J ) 6.7 Hz)
4.85 (d,d, J ) 5.7, 9 Hz) C,H
4.79 (t, J ) 6 Hz)
4.85 (t, J ) 6.5 Hz)
4.85 (t, J ) 6.5 Hz)
4.76 (t, J ) 6 Hz)
4.84 (t, J ) 6.7 Hz)
4.79 (t, J ) 5.9 Hz)
4.80 (t, J ) 6.6 Hz)
OMe Me R(â)
OMe Me R(R)
Cl
Cl
F
27H38O8
H
H
H
H
H
H
H
S(â)
R(â)
R(â)
S(â)
R(â)
S(â)
25H33O7Cl
25H33O7Cl
25H33O7F
25H33O7F
25H33O7Br
25H33O7Br
C,H,Cl
C,H,Cl
C,H
F
C,H
Br
Br
OMe
C,H,Br
C,H,Bra
C,H
6g
6h
R(â) C26H36O8
a
Calcd for Br ) 15.24, found 14.32.
Ta ble 2. In Vitro Antimalarial Activity against P. falciparum
IC50 (ng/mL) IC50 (ng/mL)
point, solubility, and Rf values on TLC. Thus, the
diastereomers of compounds 5 were successfully sepa-
rated by the use of a normal phase silica gel chroma-
totron, preparative TLC, or column chromatography.
The hydrolysis of 5 with 2.5% KOH/MeOH gave the
corresponding carboxylic potassium salt which was
converted to the free carboxylic acids by addition of
dilute HCl to give 6. The identities of all products were
established by 1H-NMR (Table 1) spectrometry and
elemental analysis.
compd
W-2
D-6
compd
W-2
D-6
artemisinin
artelinic acid
2.138
1.380
3.912
4.070
0.903
0.7275
0.3910
0.4305
0.6158
0.6727
1.0095
5h
6a
6b
6d
6e
6f
0.6468
1.261
0.357
1.339
0.828
0.313
0.419
3.452
0.8266
2.403
0.380
2.210
2.332
0.405
1.359
3.816
5a
5b
5c
5d
5e
5f
0.7940
0.6290
0.6560
0.3980
0.4878
0.5433
0.6200
6g
6h
5g
The proton NMR spectra of R- and S-diastereomers
of 5 and 6 displayed large chemical shift differences (∆
ppm) from signals of C10-H and C12-H of the dihydro-
artemisinin moiety as were observed previously for this
type of compounds. The proton signals of C10-H from
R-isomers resonate 0.4-0.5 ppm upfield from those of
the corresponding S-isomers. On the contrary, the
proton signals from C12-H of R-diastereomers are 0.4-
0.6 ppm downfield from those of S-diastereomers. The
substantial differences in chemical shifts observed
between R- and S-diastereomers of the related analogs
7 were found, by X-ray crystallographic data, to be due
to conformational differences in both diastereomers.22
The aromatic ring of the R-isomer of compound 7 is
positioned over the C10-H and away from C12-H. On the
other hand, the benzene ring of the S-isomer is posi-
tioned over C12-H and away from C10-H. The diamag-
netic anisotropic effects of the benzene ring, therefore,
shielded the C10-H in the R-isomer and C12-H in the
S-isomer which lead to the observed differences in their
chemical shifts. It is interesting to note that the
benzene ring of these new compounds also exerts a
shielding effect to the C9-CH3 protons of the R-isomers,
causing an increase in chemical shift differences be-
tween R- and S-isomers from less than 0.05 ppm to 0.15
ppm.
Resu lts a n d Discu ssion
The new dihydroartemisinin derivatives were tested
in vitro against two clones of human malaria, P.
falciparum D-6 (Sierra Leone I clone) and W-2 (Indo-
china clone). The former clone is a strain that is
resistant to mefloquine and the latter to chloroquine,
pyrimethamine, sulfadoxine, and quinine. As shown in
Table 2, all new compounds demonstrated activity
2-10-fold better than that of artelinic acid or artemisi-
nin against both clones. The esters 5a -h and three of
the free acid analogs 6b, 6f, and 6g with IC50 values
less than 1 ng/mL are as active as the lipophilic
arteether. It was observed previously in this laboratory
that conversion of esters to free carboxylic acids of
compounds with smaller molecular weight than those
in this study, such as methyl artelinate and related
compounds, reduced antimalarial activity severalfold.
This observation was used as a basis in this study to
design compounds with higher lipophilicity than arte-
linic acid by increasing the length of the aliphatic acid
side chain which compensates for the loss of lipophilicity
on conversion of the ester to acid. The antimalarial
results indicated that both esters (5b and 5f) and acids
(6b and 6f) of Cl and Br analogs of the new compounds

Notes
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9 1399
Ta ble 3. In Vivo Antimalarial Activity against Plasmodium
berghei and the Percent Suppression of Parasitemia
(6d ) and MeO (6h ) analogs are related to the longer
plasma half-life and whether the longer plasma half-
life of the compounds are a result of slower rate of
oxidative dealkylation of the side chain. The pharma-
cokinetic data may assist in further design of better and
longer acting water soluble derivatives which are devoid
of CNS toxicity.
dose
no. of
cures (C)
SD50
(mg/kg) (mg/kg)
SD90
compd (mg/kg) T/Ca
control
0
1.0
0/8
1d
56.0
n/a
16
64
2.7
4.3
0/8 (C),b 7/8 (A)c
1/8 (C), 7/8 (A)
6d
6b
6f
28.16
58.07
Exp er im en ta l Section
4
16
64
1.5
2.8
3.3
0/8 (C), 1/8 (A)
1/8 (C), 6/8 (A)
1/8 (C), 7/8 (A)
Ch em istr y. All melting points were determined on a
Mettler FP 62 melting point apparatus. Infrared spectra were
obtained on a Nicolet 20SXB FT-IR spectrometer. NMR
spectra were determined on a Brucker AC300 spectrometer
with Me4Si as an internal standard. Elemental analyses were
performed by Atlantic Microlab Inc., Norcross, GA, and the
results were within 0.4% of the theoretical values, except
where noted.
Con d en sa tion of Dih yd r oa r tem isin in (2) w ith Alco-
h ols 4. Dihydroartemisinin1 (2, 0.5 g, 1.8 mmol) was dissolved
in 70 mL of anhydrous Et2O. To the solution was added 3
mmol (excess) of an appropriate alcohol, followed by 0.25 mL
of BF3‚Et2O. The reaction mixture was stirred at room
temperature for 24 h, washed successively with 5% aqueous
NaHCO3 and H2O, dried over Na2SO4, and evaporated to
dryness under reduced pressure. The resultant crude products
were purified with a silica gel chromatotron, preparative TLC,
or silica gel column chromatography using EtOAc/hexane or
petroleum ether as eluant to give the pure single R- or
S-diastereomer. The physical properties of these compounds
and their 1H-NMR data are listed in Table 1.
Con ver sion of Ester s 5 to th e Cor r esp on d in g Ca r -
boxylic Acid s 6. Ester 5 (1 g) was dissolved in 30 mL of 2.5%
KOH/MeOH and allowed to stand at room temperature for 2
days. To the solution was added an equal volume of H2O (30
mL), and the MeOH was removed under reduced pressure.
Upon being cooled in an ice bath, the aqueous solution was
acidified with dilute HCl and extracted three times with Et2O.
The ether extracts were combined, dried over Na2SO4, and
evaporated to dryness to give crude products which were
recrystallized from appropriate solvents. The physical proper-
ties of these new acids and their 1H-NMR data are listed in
Table 1.
14.39
16.26
25.06
45.04
48.18
54.99
4
16
64
2.3
3.8
4.8
0/7 (C), 4/7 (A)
1/8 (C), 7/8 (A)
3/8 (C), 5/8 (A)
4
16
64
2.7
3.5
5.8
0/8 (C), 7/8 (A)
0/8 (C), 7/8 (A)
3/8 (C), 5/8 (A)
6h
4
16
64
1.7
2.5
4.0
0/8 (C), 3/8 (A)
0/8 (C), 8/8 (A)
1/8 (C), 7/8 (A)
a
T/C ) life span of treated mice/control. b C ) cure. c A ) active.
The terms cure and active are defined in the Experimental Section.
displayed similar in vitro activity against P. falciparum.
This is in line with the intended design to obtain an
optimal lipophilicity of the final target carboxylic acid
for better antimalarial activity. The lipophilicity of 6b
(Cl) is comparable to that of 6f (Br) and is higher than
that of artelinic acid or artemether as evidenced by the
longer retention time of the former than the latter in
reverse phase high-pressure liquid chromatography.
The in vitro antimalarial results indicated that most of
these new compounds were slightly more active against
W-2 (chloroquine-resistant clone) than against D-6
(mefloquine-resistant clone), which is in consistent with
the previous observations on related compounds of this
class.1-6
Since the main purpose of this study is to fabricate
new water soluble, stable, and long-acting dihydro-
artemisinin derivatives with minimum CNS toxicity and
the water soluble analogs are less toxic and more active
orally than the oil soluble esters, only four of the water
soluble final target compounds 6â(R) (6b, 6d , 6f, and
6h ) were selected for in vivo studies to determine their
oral activity against P. berghei.. Each of these com-
pounds cleared parasitemia rapidly and produced SD50s
and SD90s better than artelinic acid (Table 3) and
showed oral antimalarial activity at dosage of 64 mg/
kg given twice daily for 3 days. However, only Cl (6b)
and Br (6f) analogs exhibit better in vivo antimalarial
activity (3/8 cured) than artelinic acid (1/8 cured) at
higher dosage. Fluoro (strong electron-withdrawing
group) and methoxy (strong electron-donating function)
analogs are only equally active (1/8 cured) as that of
artelinic acid at the same dosing schedule. The in vivo
antimalarial activity correlates well with the in vitro
results since the Cl and Br analogs are also more active
than the corresponding F and MeO analogs in in vitro
test. As steric hindrance and lipophilicity are similar
for all four compounds, the results suggested that the
electronic effect may have played an important role in
manipulating the efficacy of this class of compounds.
Additional pharmacokinetic studies of these compounds
are currently in progress to determine whether the
higher efficacy of Cl (6b) and Br (6f) analogs than F
Biology
(a ) In Vitr o An tim a la r ia l Stu d ies. The in vitro assays
were conducted by using a modification of the semiautomated
microdilution technique of Desjardins et al.23 and Chulay et
al.24 Two P. falciparum malaria parasite clones, from CDC
Indochina III (W-2) and CDC Sierra Leone I (D-6), were
utilized in susceptibility testing. They were derived by direct
visualization and micromanipulation from patient isolates.25
The W-2 clone is susceptible to mefloquine but resistant to
chloroquine, sulfadoxine, pyrimethamine, and quinine, whereas
the D-6 clone is naturally resistant to mefloquine but suscep-
tible to chloroquine, sulfadoxine, pyrimethamine, and quinine.
Test compounds were initially dissolved in DMSO and diluted
400-fold in RPMI 1640 culture medium supplemented with 25
mM Hepes, 32 mM NaHCO3, and 10% Albumax I (Gibco BRL,
Grand Island, NY). These solutions were subsequently serially
diluted 2-fold with a Biomek 1000 (Beckman, Fullerton, CA)
over 11 different concentrations. The parasites were exposed
to serial dilutions of each compound for 48 h and incubated at
37 °C with 5% O2, 5% CO2, and 90% N2 prior to the addition
of [3H]hypoxanthine. After a further incubation of 18 h,
parasite DNA was harvested from each microtiter well using
Packard Filtermate 196 Harvester (Meriden, CT) onto glass
filters. Uptake of [3H]hypoxanthine was measured with a
Packard topcount scintillation counter. Concentration-
response data were analyzed by a nonlinear regression logistic
dose response model, and the IC50 values (50% inhibitory
concentrations) for each compound were calculated (Table 2).
(b) In Vivo An tim a la r ia l Stu d ies. The in vivo efficacy of
the artelinic acid analogs were determined in a modified
Thompson test. This test measures the survivability of mice

1400 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9
Notes
(14) Wang, T.; Xu, R. Clinical Studies of Treatment of Falciparum
malaria with Artemether, a Derivatives of Qinghaosu. J . Tradit.
Chin. Med. 1985, 5, 240-242.
(15) Lin, A. J .; Klayman, D. L.; Milhous, W. K. Antimalarial Activity
of New Water-soluble Dihydroartemisinin Derivatives. J . Med.
Chem. 1987, 30, 2147-2150.
(16) Yang, Q.; Shi, W.; Li, R.; Gan, J . The Antimalarial and Toxic
Effect of Artesunate on Animal Models. J . Tradit. Chin. Med.
1982, 2, 99-103.
(17) (a) Li, Q.; Peggins, J . O.; Masonic, K.; Brewer, T. G. Comparison
of Pharmacokinetics, Bioavailability and Hydrolysis of Dihy-
droartemisinin, Arteether, Artesunate and Artelinate in Rats.
The Annual Meeting of Amer. Soc. Trop. Med., & Hygiene,
Atlanta, GA, Oct 31-Nov 4, 1993; Paper No. 298. (b) Leskovac,
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Survival of mice to day 60 postinfection was considered a cure
(C). Compounds were considered active (A) when the survival
time of the treated mice was greater than twice the control
mice, i.e., 12-14 day.
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