Full text of DOI:10.1002/jccs.200200046

Journal of the Chinese Chemical Society, 2002, 49, 301-310
301
Invited Review
Recent Advances in Malaria Chemotherapy
Anne Robert, Odile Dechy-Cabaret, Jérôme Cazelles, Françoise Benoit-Vical, Bernard Meunier*
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse cedex 4, France
A short review of the currently used antimalarial drugs is reported. The molecular aspects of the different
possible mechanisms of action of artemisinin is documented, including recent data on heme alkylation. The
preparation and the in vitro antimalarial activity of new modular molecules named “trioxaquines” is also pre-
sented.
Scheme I Plasmodium falciparum cycle within human
MALARIA IN THE WORLD
Two billion people are now exposed to the risk of ma-
laria, more than 400 millions, WHO estimates, fall ill each
year and between 1 and 3 millions die (most of them being
African children). Malaria is the highest mortality of any par-
asitic disease and the third cause of death by infection after
tuberculosis and AIDS. These data are a low estimate. In fact,
obtaining accurate information on the rate of mortality and
morbidity is not easy, since the symptoms of acute malaria
are similar to those of many other acute infectious diseases,
and facilities for investigation of suspect cases are not easily
available, leading to an underestimation of malarial cases.1
Four different Plasmodium species are responsible for ma-
laria in man. Among them, P. malariae and P. ovale are uni-
versally susceptible to the cheap and well tolerated drug
chloroquine. P. vivax is widely extended and some cases of
resistance appeared, however it is not lethal. P. falciparum is
responsible for all the malignant cases: severe malaria (cere-
bral malaria) is an encephalopathy that, even with a suitable
treatment, can lead to death in 2-3 days (10-30% of cases).
This latter species is also involved in all main cases of drug
resistant malaria.2,3
vasion, and also gametocytes that will achieve the sexual de-
velopment of the parasite within mosquito after reabsorption
by biting the infected man.
The control of malaria largely depends on drug thera-
pies. Several classes of drugs can be considered according to
the target parasite stage.4 Schizontocides are able to inhibit
the proliferation of schizonts within red blood cells. Among
them, the quinine is still a powerful drug. This 4-quinoline-
methanol has been used as a lead structure for the design of
synthetic antimalarial agents, among them chloroquine and
mefloquine are well known (see Fig. 1 for structures).
Gametocytocides are active against sexual stages of the para-
site. Few 8-aminoquinolines exhibit this kind of reactivity
and, in this class, primaquine was found to be efficient, in-
cluding against intrahepatic stages.
Malaria is transmitted to man by the bite of an infected
female anophele mosquitoe. The parasite first invades and
develops within hepatocytes, and then colonizes erythrocytes
where is achieved its asexual multiplication (Scheme I).
Within erythrocytes, Plasmodium digests the main part of
host hemoglobin (20-80%), using the released amino-acids to
build its own proteins. The synchronous intraerythrocytic
maturation of parasites leads to the cell burst going together
with fever access and deap anemia. At each red blood cell
burst (each 48 h for P. falciparum), non mature parasites
called merozoites are released for further erythrocytic rein-
From World War II to the 1980s, the wide use of chloro-
quine for prophylaxis, associated with the fight against mos-
quitoes by draining wet lands and using insecticides such as
DDT, allowed a reduction of endemic areas. In the 1950s,
* Corresponding author. E-mail: bmeunier@lcc-toulouse.fr

302 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Robert et al.
WHO optimistically targeted malaria for eradication, and
United States and Europe got clear of malaria in the 1960s.
The first cases of resistance to chloroquine were reported in
1959 in South America, followed quickly by a report from
South-East Asia. Since then, resistance has spread through-
out those areas of the world where P. falciparum is endemic.5
Unfortunately, the rapid development of the anophele resis-
tance to pesticides that have been widely used (for instance
for soaked bed nets, resulting in some areas in a substantial
reduction of child mortality) and the resistance of P. falciparum
to the main classes of drugs (chloroquine is no longer useful
in most of the endemic areas) have quickly made the eradica-
tion out of sight. Furthermore, drug-resistant malaria is rap-
idly spreading and many regions that are now suitable might
become contaminated in the next decades.2
tivity of the bark of Cinchona, the “peruvian fever tree”. In
1820, two french pharmacists Pelletier and Caventou isolated
quinine, the alkaloid responsible for the activity. Quinine can
be used for treatment of chloroquine-resistant P. falciparum
even for children and pregnant women. However, because of
extremely bitter taste and cinchonism side effects, quinine
administration suffers from poor compliance. Furthermore,
side effects may be serious, and since the 1980s, there has
been a decline in the susceptibility to quinine7,8 but moderate
resistance can be overcome by using an association of qui-
nine with antibiotics (cyclines and, more recently, clindamy-
cine).9 As it can be used by parenteral route and is quickly ef-
ficient, quinine has been considered up to now as the best one
for severe falciparum malaria. We will see that artemisinin
derivatives are now an alternative.10
Falciparum malaria is of course a public health scourge
in endemic areas,6 but northern countries, including large
parts of Europe and United States might not be out of con-
cern, due to possible climate variations and increasing travels
in endemic regions.
Quinine was the only treatment of malaria until the
1930s, up to the development of synthetic drugs based on a
quinoline moiety, of which chloroquine, mefloquine and
amodiaquine are the most commonly used. All of them con-
tain a quinoline residue substituted at C4 by an amine or an
alcohol residue, that is a weak base function, and exhibit also
a tertiary amine function. Chloroquine (abbreviated as CQ)
has been synthesized before WWII in Germany, but it was
discarded during preliminary clinical studies. This molecule
was then patented and developed in the USA in 1944 by the
Winthrop company. First human trials were so favorable that
the Board of Economic Warfare recommended extensive tri-
als in Army and Navy both for suppression and therapy.11,12 It
has been the antimalarial drug the most widely used from this
date, but the resistance is now widespread and few countries
are unaffected.
CURRENTLY AVAILABLE DRUGS
Nearly all antimalarial drugs in current use belong to a
limited collection of chemical structures that are mainly ac-
tive against the asexual intraerythrocytic stages of the para-
site.4 The main compounds are described below.
Quinolinemethanols and 4-Aminoquinolines
A major event in the history of malaria was the discov-
ery at the beginning of the 17th century of the antimalarial ac-
Since its first use in 1986, mefloquine has been highly
efficient on erythrocytic schizonts, including on chimio-
resistant P. falciparum, and it is still a mainstay drug in case
of chloroquine resistance. However, resistance to mefloquine
appeared very quickly, specially in some areas of South-East
Asia, where this molecule can no longer be used as mono-
therapy.13,14
Amodiaquine is a 4-aminoquinoline derivative that was
introduced as an alternative to chloroquine to treat non-
complicated malaria in limited zones with low levels of
chloroquine resistance in Africa. It is a potent blood schizon-
tocide. However, resistance to amodiaquine also appeared.15
Among other aryl-aminoalcohols, halofantrine, a 9-
substituted phenanthrene derivative, is effective against
CQ-resistant malaria.16 However, cardiotoxicity has limited
its use.17 Benflumetol, a 9H-fluorenylidene derivative, is also
efficient either alone18 or in association with an artemisinin
Fig. 1. Structures of 4-aminoquinoline and quinoline-
methanol drugs.

Recent Advances in Malaria Chemotherapy
derivative.19
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 303
nate parasites at the early hepatic stage of infection, thus pre-
venting the clinical disease.31 However, general use of prima-
quine is restricted because of severe side-effects.
Mechanism of action
The drugs containing a 4-substituted quinoline moiety,
such as quinine, chloroquine, and mefloquine are able to se-
lectively accumulate within parasites. The chloroquine con-
centration in the parasite food vacuole has been estimated to
be in the millimolar range for outside concentrations in the
micromolar range.20 In vitro it has been shown that chloro-
quine and several quinoline drugs were able to interact with
high affinity with both heme and hemozoin.21-23 This interac-
The Walter Reed Institute of Research of the US Army
is now developing a new analogue, tafenoquine (WR 238605)
that is more potent than primaquine against both the liver and
blood stages of the parasite. This molecule has an improved
safety and is efficient for chemoprophylaxis against various
Plasmodium species.32,33
Artemisinin Derivatives
tion was attributed to a
stacking of the hydrophobic
Among the molecules that emerged over the past three
decades as antimalarial drugs, artemisinin occupies a particu-
lar place (see Fig. 4 for structure). The potential value of this
sesquiterpene isolated from chinese wormwood (Artemisia
annua leaf decoctions have been used in traditional chinese
medicine for the treatment of fevers for more than 2000
years).34-36 Artemisinin is present in the leaves and the flow-
ers of the plant in quantities ranging from 0.01 to 0.8% of dry
weight of materials.37,38 This trioxane is highly active against
strains of malaria that are resistant to all standard drugs and is
recommended for the chemotherapy of cerebral malaria.39
Since 1980 semi-synthetic analogues of artemisinin, arte-
quinoline residue of these drugs with the iron-protoporphyrin
IX liberated by the digestion of hemoglobin and with
hemozoin itself.24 It has been postulated that quinolines may
be able to disrupt hemozoin formation, that is a detoxification
process necessary for the parasite survival.25,26 In fact, the in-
teraction of chloroquine, or many other antimalarials, with
free heme produces “heme-drug motifs” which are probably
not incorporated in hemozoin. These “heme-drug motifs”
might represent only a small fraction of the total amount of
heme to be polymerized,27 but are probably involved in the le-
thal effects observed in infected erythrocytes.
Folate Antagonists
Antimalarial drugs belonging to the folate antagonist
class are widely used, albeit their role in malaria control is
hampered by rapid emergence of resistance under drug pres-
sure.4 For this reason, none of these drugs is used in mono-
therapy. Inhibition of enzymes of the folate pathway results
in decreased pyrimidine synthesis, hence, reduced DNA,
serine and methionine formation. Among these drugs, sul-
fonamides are competing with the substrate of dihydro-
pteroate synthase. Proguanil and pyrimethamine, mimicking
the pteridine ring of the natural substrate, inhibit the dihydro-
folate reductase. The combination of sulfadoxine and pyri-
methamine is widely used in Africa (Fig. 2).
Fig. 2. Structures of antifolate drugs.
The combination of proguanil and atovaquone (Malarone)
will provide another useful treatment.28,29 Malarone has been
approved in 2000 by U. S. Food and Drug Administration for
treatment and prevention of falciparum malaria.30
8-Aminoquinolines
Primaquine (Fig. 3), an 8-aminoquinoline, has been
shown to inhibit the development of the hepatic stages and
the gametocytes of malaria parasites, but its blood schizon-
tocidal activity is low. It is used to eliminate latent liver forms
of P. vivax and P. ovale and prevent relapses. It was recently
reconsidered for prophylaxis against P. falciparum, to elimi-
Fig. 3. Structures of 8-aminoquinolines.

304 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Robert et al.
mether and artesunate (Fig. 4), are currently used in the cura-
tive treatment of life-threatening infections with P. falciparum.
Over two million patients have been treated with artemisinin
derivatives. These compounds are well tolerated, safe for
pregnant women,40 and neurotoxicity or other major side ef-
fects in humans have not been reported until now, specially
after oral administration.3,41,42 There was also no evidence of
cardiotoxicity for the association artemether/benflumetol
(benflumetol is also named lumefantrine, and the association
artemether/benflumetol is sold under the name Riamet).43,44
Another key advantage of these endoperoxide-containing
antimalarial agents which have been used in the field for
nearly two decades is the absence of drug-resistance. At-
tempts to select artemisinin resistant strains of the human P.
falciparum parasite were unsuccessful.45 Murine malaria was
then used to study the resistance to artemisinin. When para-
sites are exposed to selection pressure within mice infected
by Plasmodium berghei or P. yoelii, a low level of resistance
has been observed which disappears as soon as the drug-
selection pressure has been withdrawn.46 Remarkably, the in-
troduction of artemisinin derivatives in routine treatment in
some areas of Southeast Asia was associated with a signifi-
cant reduction of falciparum malaria. In fact, artemisinin de-
rivatives prevent gametocyte development and therefore re-
duce the transmission.47,48 However, the relatively high cost
and erratic supply of this natural compound make necessary
the development of new synthetic and cheap endoperoxide-
based antimalarials.
rocytes. Furthermore, artemisinin is hydrophobic and local-
ized in specific parasite membranes.35 Once inside the para-
site, how artemisinin derivatives are acting? Since an arte-
misinin derivative lacking the endoperoxide bridge (deoxy-
artemisinin) is devoid of antimalarial activity,34 the reactivity
of this peroxide function within the parasite is the key factor
of the pharmacological activity of these molecules.
The target(s) of artemisinin
When artemisinin or other active trioxanes were incu-
bated at pharmacologically relevant concentrations within
human red cells infected by P. falciparum, the heme-
catalyzed cleavage of the peroxide bond was proposed to be
responsible for alkylation of heme50 and a small number of
specific parasite proteins, one of which has similar weight
than a histidine-rich protein (42 kDa).51 Another possible tar-
get protein is the translationally controlled tumor protein
(TCTP) of P. falciparum.52 It was also recently reported that
artemisinin may be involved in specific inhibition of malarial
cysteine protease activity responsible for ca 30% of hemo-
globin degradation by P. yoelii.53 Furthermore, the incubation
of purified hemozoin with artemisinin under acidic condi-
tions (pH 5), close to the pH of the parasite vacuole, resulted
in the loss of hemozoin content as compared with control, in-
dicating that hemozoin may be dismantled by interaction
with the endoperoxide-drug, and resulting in a build up of the
pool of free heme.53
In order to develop the new generations of artemisinin-
like derivatives,49 it is necessary to understand the mecha-
nism of action of artemisinin at the molecular level.
Alkylation Reactions
The importance of alkylating species generated by the
homolytic cleavage of the endoperoxide function, in particu-
lar the alkyl radical centered at position C4 of artemisinin or
related trioxanes has been early suspected.54 Alkylation of
heme by artemisinin has been reported by Meshnick et al. af-
ter identification of heme-drug adducts by mass spectrome-
try, but no structure has been proposed for the resulting cova-
lent adducts.50 It has been proposed that a high-valent
iron(IV)-oxo species might be generated during the activa-
tion of artemisinin by ferrous salts.36,55 Therefore, we decided
to investigate the reactivity of artemisinin in the presence of
reduced heme or heme models, since the high concentration
of reductants within erythrocytes (glutathione, NADPH,
etc...) is favoring the iron(II) state of heme able to mediate the
homolytic cleavage of the peroxide bond of artemisinin.56
Because of the variety of possible alkylation sites on proto-
porphyrin IX, we first decided to investigate the alkylating
activity of artemisinin with manganese(II) tetraphenylpor-
phyrin, a synthetic metalloporphyrin having a fourth order
symmetry and only eight equivalent -pyrrolic positions as
Mechanism of action of antimalarial endoperoxides
Artemisinin and its derivatives are toxic to malaria par-
asites at nanomolar concentrations, whereas micromolar con-
centrations are required for toxicity to mammalian cells. One
reason for this selectivity is the enhanced uptake of the drug
by the parasite: P. falciparum infected erythrocytes concen-
trate [3H]-dihydroartemisinin and [14C]-artemisinin to more
than 100-fold higher concentration than do uninfected eryth-
Fig. 4. Structures of artemisinin and its main deriva-
tives.

Recent Advances in Malaria Chemotherapy
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 305
possible alkylation target. Manganese was choosen as central
metal instead of iron because of easier removal from the
porphyrin ligand for NMR characterization of an expected
alkylation derivative. By reacting MnIITPP with artemisinin,
artemether, or several synthetic trioxanes, chlorin-type ad-
ducts were formed by reaction of the macrocycle with an
alkyl radical generated by reductive activation of the perox-
ide of the drug.57,58 The mechanism of formation of the
artemisinin- and artemether-TPP adduct is reported in Fig. 5
[it should be noted that the reduction of the porphyrin macro-
cycle to a chlorin involved the borohydride initially used to
generate MnIITPP from MnIII(TPP)Cl. However, in the ab-
sence of a hydride able to trap the cation generated at C3 , a
proton released at C2 can regenerate the porphyrin ring. This
rearomatization of the macrocycle was competitive with the
hydride reduction step, and a ratio chlorin-/porphyrin-adduct
of 85/15 to 75/25 was obtained in the activation of trioxane
BO7 by MnIITPP.58]
entation (i.e. on the same side of the endoperoxide with re-
spect to the mean plane of the drug) were biologically inac-
tive and also unable to alkylate the macrocycle (Fig. 6).
These data confirmed that a close interaction between the
metal center and the peroxide bond is required, suggesting
that this activation occurred through an inner-sphere electron
transfer. The alkylation ability which is considered as crucial
for the antimalarial activity of artemisinin is not limited to
this natural compound, but is a general feature required for
the biological activity of endoperoxide-containing antimalar-
ial drugs.
It was of particular interest to investigate the reactivity
of artemisinin toward iron(II)-heme itself, the biological acti-
vator and an expected target of this antimalarial drug. For this
purpose, iron(III) protoporphyrin IX dimethylester was re-
acted with artemisinin (or artemether) in the presence of a
hydroquinone derivative (or with a thiol) used as mild reduc-
ing agent to generate the iron(II) heme. Heme was readily
converted to heme-artemisinin (or heme-artemether) adducts
in high yield.62 The demetallation of this mixture of three ad-
ducts followed by NMR characterization indicated that the
-, -, and -meso carbons were preferentially alkylated
(Fig. 7).63
By studying a large series of trioxanes,58-61 it has been
possible to correlate the alkylating ability toward MnIITPP
and the pharmacological activity, the inactive drugs being un-
able to efficiently alkylate the porphyrin ring. Furthermore, it
appeared that trioxanes bearing a bulky substituent in ori-
Fig. 5. Alkylation of MnIITPP by artemisinin or artemether after reductive activation of the peroxide function.

306 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Robert et al.
It is remarkable that no bis-alkylated adducts could be
obtained neither with heme nor with the heme model
MnIITPP, even in the presence of an excess of drug, although
the metal center keeps redox properties after the first alkyla-
tion. This means that a bulky drug-derived substituent at the
periphery of the macrocycle precludes the close interaction
of a second drug molecule required for bis-alkylation. This
phenomenon is probably similar to the in vivo sterically hin-
dered stacking of heme-drug adducts leading to accumulation
of non-polymerizable redox active heme adducts.
via a thioether linkage.
ANTIMALARIAL THERAPY FOR TOMORROW
Drug Combination
It is now the WHO policy to develop the use of these
artemisinin derivatives as first-intention drugs to treat severe
malaria. In fact, the association of two antimalarial molecules
should allow to improve the treatment efficacy and to avoid
the emergence of resistant strains.66 If one parasite is resistant
to a drug A in a population of 109 parasites, and one parasite
resistant to a drug B in a population of 109 parasite, only one
in a population of 1018 parasites will be resistant to both drugs
A and B. Each ill person being carrier of 108 to 1012 parasites,
the probability of simultaneous resistance to two drugs acting
with different modes is close to zero.6
In fact, the artemisinin chemistry generated by the
monoelectronic reduction of the peroxide bridge in the pres-
ence of iron hemin or models can probably be considered as a
radical chemistry occurring within a limited space like in a
cage and, therefore, with a relatively high selectivity. Such
reported results suggest that in vivo the low and transient con-
centration of free heme generated by hemoglobin digestion is
probably able to perform the reductive activation of the
peroxide bond of artemisinin and active trioxanes. This
pathway will generate alkylating species such as radical 3,
and is likely to disrupt vital biochemical processes of the
parasite via alkylation of biomolecules. The alkylating
properties of the radical 3 has also been evidenced by isola-
tion of covalent adducts with cysteine64 or glutathione65
The associations that are now the most widely used are
pyrimethamine + sulfadoxine, chloroquine + proguanil, and
atovaquone + proguanil (atovaquone is a hydroxynaphtho-
quinone derivative). However, these associations are poorly
Fig. 7. (a) Formation of a C4-centered radical after
reductive activation of the endoperoxide func-
tion, leading to a (b) covalent adduct by alkyla-
tion of heme-dimethylester.
Fig. 6. Activation of synthetic trioxanes by inner-
sphere electron transfer: correlation between
antimalarial activity and alkylating properties
toward a heme model.

Recent Advances in Malaria Chemotherapy
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 307
active against strongly chloroquine-resistant strains. Arte-
misinin (or its derivatives) associated with mefloquine are
currently used against multiresistant strains of P. falciparum.67,68
Furthermore, it appeared that this association is able to stop
the progression of mefloquine resistance.13,69
sistant strains: substitutions in the quinoline nucleus, varia-
tions in the side chain,75,76 synthesis of polyquinolines77 and
introduction of a ferrocenyl moiety.78 Such modifications
seem to be enough to make a compound that is active on resis-
tant strains but the request for a safe and effective chloro-
quine alternative is still going on. Artemisinin and deriva-
tives (artemether, arteether, artesunate) are more and more
used in Asia and Africa where multidrug resistant P.
falciparum is prevalent. But this series of molecules, as well
as recent other antimalarial derivatives,79,80 is based on
artemisinin itself, a molecule having a very short life time in
plasma.81 Furthermore, the artemisinin production is mainly
limited to China and Vietnam, that is a handicap for other
countries. An alternative is the development of synthetic
trioxanes, simplified analogues of artemisinin retaining the
crucial endoperoxyde bridge, but up to now none of them has
entered successfully in clinical trials.3,49
Vaccines
A lot of efforts have been made for elaboration of ma-
laria vaccines without success until to now.70,71 In fact, none
of the available in vitro assays are predictive of functional
immunity in vivo, and there is no reliable animal model. Fur-
thermore, the cycle of Plasmodium is complex, the several
stages in human are morphologically and antigenically dis-
tinct, and that obliges to conceive multivalent antigen vac-
cines. The near availability of the complete sequencing of the
genome of P. falciparum should improve the chances of exist-
ing of a vaccine.72 It must be mentioned that HIV genome
(very short: less than 10.000 bases) has been known for more
than 15 years without facilitating the preparation of a vaccine
or new drugs able to definitively cure the disease.
New Modular Drugs: “Trioxaquines”
Keeping in mind that heme liberated in the parasite
food vacuole is a target of special interest, there are good ar-
guments for combining an artemisinin derivative to all newly
introduced antimalarial drug to delay or even prevent the de-
velopment of resistance.66 We adopt this therapy approach by
preparing new chimeric molecules by covalently attaching a
trioxane moiety to a 4-aminoquinoline entity.82 These mole-
cules, named trioxaquines (Fig. 8a) were designed according
to what we know about the mechanism of action of artemis-
inin and chloroquine derivatives: they combine a peroxidic
entity acting as a potential alkylating agent and an amino-
quinoline known to easily penetrate within parasites.25 This
strategy involves two active entities, that of chloroquine and
that of artemisinin, in a single molecule. Better than a simple
combination, this “covalent bitherapy” is supposed to consid-
erably reduce the risk of drug resistance. Furthermore, the in
vivo half-live of artemisinin derivatives is short (less than 3
hrs),81 leading to recrudescences when these compounds are
The falciparum genome sequencing will also allow the
identification of new parasite proteins to be inhibited. But
time is long from discovering targets to develop new thera-
peutic agents, and high costs are likely for this approach.73
Old Targets, New Compounds
An alternative strategy is the exploitation of known tar-
gets: recently discovered targets as the phospholipid (PL)
metabolism of infected erythrocytes or old classical targets as
the free heme in the food vacuole. The PL metabolism of in-
fected erythrocytes is an effective pharmacological target be-
cause of its specificity: malaria parasite needs large amounts
of phospholipids, mainly phosphatidylcholine (PC) to grow
and divide. The supply of PC, vital for the parasite, is
achieved via a choline carrier. Quaternary ammonium and
bis-ammoniums salts, designed as choline analogues to target
this choline carrier, are highly active in vitro even against
multi-resistant isolates.74 Interesting results have been ob-
tained in this family of compounds, encouraging further re-
search in this direction.
The free heme liberated in the parasite food vacuole is
an “old” but always attractive pharmacological target: it is
the most specific target that can be exploited since it comes
from the hemoglobin digestion by the parasite, that occurs
only in infected erythrocytes. Many chemical entities are di-
rected toward this now well-known target, among them
chloroquine and derivatives and artemisinin and derivatives.
Many quinoline modifications have been investigated to ob-
tain a molecule as affordable as chloroquine and active on re-
Fig. 8. (a) General structure of trioxaquines. (b) Struc-
tures of trioxaquines DU-1102 and DU-1108.

308 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Robert et al.
Enserink, M. Science 2000, 290, 428-441.
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able pharmacokinetics for trioxaquines compared to that of
artemisinin.
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For obvious reasons, these molecules must be cheap to
prepare and easily accessible: thus we used a convergent syn-
thesis based on classical reactions. Many simple modulations
(quinoline, diamine, diene, diketone) are possible, leading to
a large family of new potential antimalarial compounds. The
first synthesized trioxaquines (Fig. 8b) have been tested in vi-
tro on laboratory strains (chloroquine-sensitive and chloro-
quine-resistant ones) of P. falciparum: all IC50 values ob-
tained were below 30 nM, without any significant difference
between sensitive and resistant strains.82 DU-1102 has also
been tested in vitro on human isolates in Yaoundé (Camer-
oon) and was found to be highly active, with IC50 values rang-
ing from 11 to 70 nM, without any significant difference be-
tween chloroquine- and pyrimethamine-sensitive and resis-
tant strains.83 No significant cross-resistance was observed
with chloroquine and pyrimethamine.
We are currently working on the in vivo evaluation of
these modular trioxaquines, and one was found to be highly
active by oral route in mice. These encouraging results vali-
date this strategy of “covalent bitherapy” and indicate a
promising future for these drug candidates that can be devel-
oped for clinical trials in a reasonable future in collaboration
with a newly created company named Palumed.84
ACKNOWLEDGEMENTS
CNRS is acknowledged for financial support, and the
French Ministery of Education for Ph D grants to JC and
ODC. The synthetic trioxanes described in Fig. 6 were kindly
provided to us by G. H. Posner (Baltimore). He is also grate-
fully acknowledged for the high quality of scientific discus-
sions and exchanges.
19. van Vugt, M.; Brockman, A.; Gemperli, B.; Luxemburger,
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Received October 31, 2001.
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Key Words
Artemisinin; Malaria; Peroxide; Quinoline;
Trioxaquine.
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