KOE423/3

SELECTED TOPIC IN
ORGANIC CHEMISTRY

ANTIMALARIALS

PREPARED BY: ROGER KHO TAI LEONG

(130107)

LECTURER: DR. MOHAMAD NURUL

AZMI BIN MOHAMAD TAIB
1. INTRODUCTION
Malaria is one of the most common infectious diseases and a great public
health problem worldwide, particularly in Africa and south Asia. About three
billion people are at risk of infection in 109 countries. Each year, there are an
estimated 250 million cases of malaria leading to approximately one million
deaths, mostly in children under five years of age. Its symptoms include fever,
tiredness, vomiting and headaches.

The organism that causes the most dangerous form of malaria is a microscopic
parasite called Plasmodium falciparum. This parasite is commonly
transmitted by a female mosquito species belonging to the Anopheles genus.

There is growing international agreement on how best to use prevention and

treatment methods that are available. The most effective prevention measures
include the use of mosquito bed nets treated with long-lasting insecticides –
to avoid the mosquito bites and to kill the mosquitoes – and spraying the inside
walls of houses with similar insecticides to kill malaria-carrying mosquitoes.

The most effective treatment for malaria consists in using a combination of

several anti-malarial drugs that include artemisinin., mefloquine, lumefantrine
or sulfadoxine. Preventive treatment of pregnant women with anti-malarial
drugs can also reduce the harmful effects of malaria both on the mother and
on the unborn child.

In this chapter, we will focus on the synthesis mechanism of artemisinin,

mefloquine and lumefantrine.
2. LITERATURE REVIEW
a) Artemisinin
Artemisinin (Fig. 1) is isolated from the plant Artemisia annua
(qīnghāosù), the sesquiterpene artemisinin exhibits excellent anti-
malaria activity and kills the parasite at most of its asexual stages of
development in human blood[1]. Artemisinin-based combination
treatments (ACTs) are widely used as the first-line treatment for
malaria[2]. Despite of several synthetic routes to artemisinin have been
developed[3], the chemical synthesis is lengthy and low yielding due to
the highly complex structure of the sesquiterpene endoperoxide.
Consequently, the world market price is high ranging from US $350 to
$1700 per kilogram[4]. However, most affected countries are in the
developing stage, and therefore a stable and affordable supply of
artemisinin is utmost vital. Currently, the most efficient synthetic route
to produce artemisinin is the combination of a biosynthesis process with
several chemical steps.

Fig. 1: Artemisinin

b) Mefloquine
Like artemisinin, mefloquine (MQ) is also an antimalarial drug but it is
particularly efficient against chloroquine-resistant strains of malaria
parasites. In addition to its longer half-life as compared to others
antimalarial drugs, MQ is safe in the second half of pregnancy[5]. MQ
is a α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and
 possesses two asymmetric carbon atoms. It exists under two racemic
forms, erythro and threo, each one composed of a pair of enantiomers
(Fig. 2). In clinical practice, MQ is commonly used as a racemic
mixture of erythro enantiomers.

Fig.
2: Optical isomer of mefloquine

c) Lumefantrine
Lumefantrine is also used in the prevention and treatment of Malaria in
worm blooded animals. It is chemically known as 2-(dibutylamino)-1-
[(9Z)-2, 7-dichloro-9-(4-chlorobenzylidene)-9H-floren-4-yl] ethanol
(Fig. 3).

Fig. 3: Lumefantrine
3. SYNTHESES OF SELECTED DRUG
a) Artemisinin

Scheme 1: Synthesis of artemisinin from farnesyl diphosphate (2)

The first step of synthesis involves the class I sesquiterpene cyclase

amorphadiene synthase (ADS). This enzyme catalyzes the cyclisation
of (E, E)-farnesyl diphosphate (FDP, 2) to amorpha-4-11-diene (3), a
bicyclic intermediate with four stereocentres. 3 can be converted to the
advanced synthetic intermediate dihydroartemisinic acid (DHAA, 4)
either chemically or enzymatically using engineered yeast.

Scheme 2: Schematic synthesis of artemisinin (1) from 12-hydroxyfarnesyl diphosphate (6).

Scheme 2 shows a novel synthesis route to artemisinin (1) from the

oxygenated farnesyl diphosphate analogue 12-hydroxyfarnesyl
diphosphate (6). Amorphadiene synthase (ADS) can convert 6 in a
single step to dihydroartemisinic aldehyde (DHAAl, 7), an advanced
intermediate of artemisinin[6]. Unlike scheme 1, this route does not
 proceed via amorphadiene (3) and therefore avoids several redox steps.
Increasing the oxidation state at the linear precursor stage produces a
two-step synthesis of 4, which significantly shortens the synthesis of
artemisinin (1).

b) Mefloquine

Scheme 3: First synthesis of (±)-erythro-MQ[7]

As shown in scheme 3, this synthesis begins with the condensation of

p-trifluoromethylaniline with ethyl 4,4,4-trifluoroacetate in the
presence of polyphosphoric acid to provide a 4-quinolone which was
converted to 4-bromoquinoline 3 using POBr3. A carboxylation
reaction led to cinchonic acid 4 with 86% yield. Addition of 2-pyridyl
lithium salt to this acid provided a pyridylketone 5 which, is reduced
with H2/Pt, gave MQ. This stereospecific reduction led only to the
erythro enantiomers.

c) Lumefantrine

Scheme 4: Synthetic Scheme For Lumefantrine[8]

Generally, the substance 2 undergoes Friedel-Crafts acylation followed
by hydrolysis to form hydroxide with sodium borohydride. The
terminal chlorine is then replaced with disubstituted alkyl nitrogen.
Lastly, the substance 5 is converted to Lumefantrine by substituting the
hydrogen with longer benzyl compound at cyclopentadiene sites.
4. REFERENCES
1. Terkuile, F., et al., Plasmodium falciparum: In Vitro Studies of the
Pharmacodynamic Properties of Drugs Used for the Treatment of
Severe Malaria. Experimental Parasitology, 1993. 76(1): p. 85-95.
2. Klayman, D.L., Qinghaosu (artemisinin): An antimalarial drug from
China. Science, 1985. 228(4703): p. 1049-1055.
3. Zhu, C. and S.P. Cook, A Concise Synthesis of (+)-Artemisinin. Journal
of the American Chemical Society, 2012. 134(33): p. 13577-13579.
4. White, N.J., Qinghaosu (Artemisinin): The Price of Success. Science,
2008. 320(5874): p. 330.
5. Nosten, F., et al., Mefloquine prophylaxis prevents malaria during
pregnancy: a double-blind, placebo-controlled study. Journal of
Infectious Diseases, 1994. 169(3): p. 595-603.
6. Demiray, M., et al., An Efficient Chemoenzymatic Synthesis of
Dihydroartemisinic Aldehyde. Angewandte Chemie International
Edition, 2017. 56(15): p. 4347-4350.
7. Lutz, R., C. Ohnmacht, and A. Patel, Antimalarials. 7. Bis
(trifluoromethyl)-. alpha.-(2-piperidyl)-4-quinolinemethanols. Journal
of medicinal chemistry, 1971. 14(10): p. 926-928.
8. Pharma, D., et al., Synthesis and characterization of novel related
substances of Lumefantrine, an anti-malarial drug. Vol. 8. 2016. 91-
100.