MEDICINAL CHEMISTRY

OF ANTIMALARIALS

Kim J.B.

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What is Malaria?
• Is a vector born infectious disease caused by protozoan parasites
(female anopheles mosquito). (Vector means, it does not cause disease
itself but spread infection by conveying pathogens from one host to
another)
• It is widespread in tropical and subtropical regions
• Four species of the genus plasmodium infect the humans, they are: P.
falciparum, P. vivax, P. ovale and P. malariae.
• P. falciparum is the most deadly malaria parasite and most prevalent in
Africa.
• P. vivax is the most common cause of relapse if treatment was not
completed.
• Although infections with the fifth parasite P. knowlesi, is an important
cause of human malaria in the islands of Borneo and Peninsular Malaysia.
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Parasitic infection caused by various species of Plasmodium - transmitted
via bite of female anopheles mosquito

Symptoms:
High/periodic fever
Headache
Chills
Anorexia
Body ache
Fatigue

P. falciparum may progress to severe malaria xtized by:

Metabolic acidosis
Anaemia
Delirium and even death

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Malaria Globally and in Nigeria

• Globally, 3.3 billion people at risk

• 228 million cases in 2018, 405,000
deaths (WHO, 2019)
• Sub-Saharan Africa & parts of Asia
most affected.
• 80% of cases & 90% of deaths occur in
Africa.
• Nigeria average prevalence rate is 71%.
• Nigeria recorded 35% malaria death in 2015.
• Malaria is responsible for 60% outpatient visit to health facilities, 30%
childhood death in children under 1 year and 11% maternal death.
• The financial loss due to malaria annually is estimated to be about 132billion
Naira in form of treatment cost, prevention, loss of man hours etc.
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Human species:

• Plasmodium falciparum (Malignant tertian malaria)

• Plasmodium vivax (Benign tertian malaria)

• Plasmodium ovale (tertian fever)

• Plasmodium malariae (Quartan malaria)

• Plasmodium knowlesi

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MALARIA CONTROL STRATEGIES
• Promotion of environmental sanitation
• Use of insecticides
• Indoor residual spraying with insecticides e.g. DDT, Pyrethroids
• Use of insecticide treated nets (ITN’s & LLITN’s)
• Biological Control
• Genetically modified mosquitoes
• Malaria Vaccines development
• Intermittent Preventive Therapy (IPTi & IPT)
• Pharmacotherapy

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Life Cycle of Plasmodium parasite

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Classification of Antimalarials
• May be classified on the basis of:
• Stage of parasite life cycle on which they act
• Blood Schizonticides e.g. Chloroquine, quinine, artemisinins
• Tissue Schizonticides e.g. Primaquine
• Gametocytocides e.g. - Chloroquine & Quinine – P. vivax & P. ovale
• Primaquine – gametocytocidal on all human malarial parasites
• Sporontocides e.g. Primaquine and Chlorproguanil
• Two important concepts:
• Clinical cure
• Radical cure

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Chemical Classification of Antimalarials
• 1. Cinchona Alkaloids e.g. Quinine, Quinidine
• 2. 4-Aminoquinolines e.g. Chloroquine, Amodiaquine, Sontoquine
• 3. 8-Aminoquiolines e.g. Primaquine, Tafenoquine, Bulaquine
• 4. Quinoline Methanols e.g. Mefloquine
• 5. Phenanthrene methanols e.g. Halofantrine
• 6. Sulphonamides & Sulphones e.g. Sulphadoxine, Dapsone
• 7. Diaminopyrimidines e.g. Pyrimethamine
• 8. Biguanides e.g. Proguanil, Chlorproguanil, Cycloguanil
• 9. Naphthoquinones e.g. Atovaquone
• 10. Sesquiterpene lactone e.g. Artemisinin, Artemether, Artesunate
• 11. Antibiotics e.g. Doxycycline, Clindamycin, Ciprofloxacin
• 12.07/31/2022
Acridines e.g. Mepacrine Kim J. B. 10
1. Cinchona Alkaloids

• Four alkaloids produced by the Cinchona tree Cinchona officinalis.

• Enantiomeric pair quinine and quinidine and their desmethoxy
analogues cinchonidine (for quinine) and cinchonine (for quinidine)
• Have four (4) asymmetric Carbon centres.
• Quinine is the most used but is less potent and less toxic than
Quinidine.

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SAR of Cinchona Alkaloids…
• Modification of the sec-alcohol at C-9 through oxidation, esterification etc
diminishes activity.
• The quinuclidine portion is not necessary for activity
• An alkyl tertiary amine at C-9 is important for activity.
• Oxidation of the vinyl group (-CH=CH2) to carboxyl (-COOH) group (as in
quitanine) leads to complete loss of activity.
• Esterification of the carboxyl group restores the activity partially.
• Demethylation of quinine with HBr/AcOH or BCl3 in CH2Cl2 yield cupreine (A
natural alkaloid obtained in cuprea bark) with remarkable reduction in activity.

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Cinchona Alkaloids….
• Mechanism of Action
• Similar to Chloroquine ( see next group)
• Metabolism
• Quinine is metabolized in the liver by CYP3A4 to the 2’-hydroxy derivative
• Followed by additional hydroxylation on the quinuclidine to give the 2,2’-
dihydroxy derivative as the major metabolite
• Side Effect
• Cinchonism: a toxic syndrome - tinnitus, headache, nausea, and disturbed
vision.
• Can also cause premature contractions in late pregnancy.
• Quinine is an effective Blood schizonticide
• Quinidine is used as an antiarrhythmic – importance of stereochemistry.

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2. 4-Aminoquinolines
• Developed based on the Quinine structure
• Examples: Chloroquine, Amodiaquine, Sontoquine.
• Have an asymmetric centre a position C-9.
• Both isomers are active and is commonly used as a racemic mixture.
• The 7-Chloro group and terminal amino group are important for
activity.
• Alkylation at C-3 and C-8 diminishes activity.

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4-Aminoquinoline…
• Formulated as the phosphate or hydrochloride salt.
• Mode of Action
• Accumulates in the acidic food vacuole (pH 5.5) and interferes
with the process of haem detoxification.
• The drugs form a complex with haem in which the aromatic
quinoline ring π bonds to the porphyrin nucleus

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4-Aminoquinolines….
• Chloroquine is the most important member but its use has
diminished due to extensive resistance.
• Reduced uptake and transport of chloroquine to food vacuole of
plasmodium.
• Hydroxychloroquine is less toxic but mostly used for treating
rheumatoid arthritis.
• Metabolism
• It is metabolized via N-dealkylation by CYP2D and CYP3A4 isoforms
• Other Uses of CQ
• Extraintestinal amoebiasis/Hepatic amoebiasis
• Rheumatoid arthritis
• Discoid lupus erythematosus

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4-Aminoquinolines…
• Amodiaquine
• Amodiaquine is similar to Chloroquine but is associated with a
higher incidence of hepatitis than CQ due to quinone imine
formation.

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4-Aminoquinoline…
• Synthesis of Amodiaquine
• Paracetamol undergoes amino-methylation reaction (Mannich
reaction) using formaldehyde and diethylamine.
• Saponification of this with sodium hydroxide gives the amino
derivative, which in turn reacts with 4,7-dichloroquinoline to
afford amodiaquine.

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3. 8-Aminoquinolines
• Similar to the 4-aminoquinolines
• E.g. Primaquine: 6-methoxy-8-(4-amino-1-methylbutyl)
aminoquinoline.
• They are all active against the liver forms of the parasite
• latent tissue forms of P. vivax & P. ovale (Hypnozoites)
• hepatic stage of P. falciparum
• They are inactive against the erythrocytic stage of the parasite
but gametocidal against all strains of Plasmodium.
• All can cause haemolytic anaemia in erythrocytic glucose-6-
phosphate dehydrogenase (G6PD) deficient patients.

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8-Aminoquinoline…
• All agents in this series have a five Carbon alkyl linkage or bridge
between the two Nitrogen atoms.
• With the exception of pentaquine, the other three have one
asymmetric carbon.

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8-Aminoquinoline…
• Primaquine is the most popular member of this class in current
clinical use for clearing the hepatic forms of the parasite (tissue
schizonticide).
• Mechanism of Action
• Poorly understood
• May involve disruption of the parasite mitochondria.
• May generate reactive oxygen species (ROS) which cause oxidative damage
to the essential cellular components of the parasite
• Primaquine is metabolized into carboxyprimaquine (major
metabolite) and N-acetylprimaquine, hydroxyprimaquine and
conjuates as minor metabolites.

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8-Aminoquinoline….
• Tafenoquine:
• More active slowly metabolized analog of primaquine
• has advantage that it can be given on weekly basis.
• Bulaquine:
• Congener of primaquine
• Comparable antirelapse activity when used for 5 days
• Partly metabolized to primaquine
• Better tolerated in G6PD deficiency

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4. Quinoline Methanols
• Mefloquine
• (2,8-bis(trifluoromethyl)quinolin-4-yl](piperidin-2-yl)methanol)
• Chemically related to quinine
• Synthesized with the intention of blocking the metabolism of Quinine with
the chemically stable –CF3 group.
• Fast acting Blood schizonticide
• Chiral molecule with two asymetric carbon centres, which means it has four
different stereoisomers.

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Quinoline Methanols….
• Mechanism of Action
• Same as chloroquine
• Pharmacokinetics
• Lipophilic in nature and presence of food enhances its absorption
• Metabolized to carboxymefloquine
• Extensive tissue binding with low clearance
• Side Effects
• Neuropsychiatric: seizures, suicidal tendencies
• CVS: arrhythmias
• Dermatologic: rash, pruritus
• GIT: nausea and vomitting, diarrhoea

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5. Phenanthrene Methanols
• Halofantrine
• Unknown mechanism of action
• Used in chloroquine resistant malaria since 1980
• Erratic bioavailability and lethal cardiotoxicity have limited its use.
• Lumefantrine which is structurally related has been developed.

Halofantrine Lumefantrine
• Lumefantrine has a long half life (3-6 days) & is usually combined with short acting
Artemisinins (Artemether)
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6. Sulphonamides & Sulphones
• Act by inhibiting the parasite’s
diydropteroate synthetase enzyme
• Not used alone but combined
with Pyrimethamine.

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7. Diaminopyrimidines
• E.g Pyrimethamine
• Mechanism of Action
• Interferes with the DNA synthesis by competitively inhibiting the
enzyme dihydrofolate reductase (DHFR).
• Effective against erythrocytic forms of all species.
• Used in combination with Sulphadoxine for sequential blockade

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8. Biguanides
• Proguanil :
• Inhibitor of dihydrofolate reductase
• Prodrug converted to cycloguanil (active compound)
• Act slowly on erythrocytic stage of P. vivax & falciparum
• Not a drug for acute attack due to slow action
• Usually combined with Atovaquone

• Synthesis of Proguanil

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9. Naphthoquinones
• Atovaquone (Synthetic napthoquinone)
• Rapidly acting blood schizonticide for Plasmodium falciparum &
other plasmodia
• Mechanism of Action
• Collapses mitochondrial membrane &
interferes ATP production by inhibition
of cytochrome c 0xidoreductase.

• Proguanil potentiates action of atovaquone and prevents

development of resistance (Malarone)
• Also used in P. Jiroveci & Toxoplasma gondii infection

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10. Sesquiterpene Lactones
• Artemisinin is the active principle of the plant Artemisia annua
(sweet wormwood)
• Most potent and rapid acting blood schizonticide
• Sesquiterpine lactone derivative
• Complex tetracyclic structure &
contains a 1, 2, 4 trioxane &
a lactone ring with seven asymmetric
centers
• Limitations
• Short half life in vivo
• High recrudescence rate
• Poorly soluble in water & oil
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SAR of Artemisinin Derivatives
• The endoperoxide bridge within the trioxane ring is
essential for activity; derivatives in which the
endoperoxide is modified e.g. deoxyartemisinin (1)
are inactive.

• The lactone ring B is not required for activity as demonstrated by the high
activity of deoxoartemsinin (5)
• Similarly, ring D is NOT required for activity as the tricyclic derivative (6) is
as active as ART - Artemisinin.

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SAR of Artemisinin derivatives…
• The methyl group on ring A is NOT required
for activity. D
• The non-peroxide ketal oxygen atom at the 4 A

position of the 1,2,4-trioxane ring is necessary C

B
for optimal activity as the 1,2- dioxane
derivatives (7) are less potent than the
parent 1,2,4- trioxanes.
• Artemisinin was the lead compound for the development of new
derivatives with improved pharmacokinetic properties.
• The lactone can be reduced to give
dihydroatermisinin (DHA) which
retains activity.
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SAR of Artemisinin derivatives…
• Reduction of artemisinin to dihydroartemisinin introduces another
chiral center and gives rise to epimers (α and β) – both
stereoisomers being active.
• DHA can also be used to prepare semi-synthetic derivatives with
improved pharmacokinetic properties. E.g. Artesunate is the water
soluble hemisuccinate ester of Artemisinin while Artemether and
Arteether are oil soluble ether derivatives.

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MoA of Artemisinin Derivatives
• Their action is linked to the presence of the endoperoxide bridge
• Endoperoxide bridge interacts with heme in parasite
• Heme iron cleaves this endoperoxide bridge
• There is generation of highly reactive free radicals which damage
parasite membrane by covalently binding to membrane proteins

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Artemisinin Based Combination Therapy (ACT)
• Artemisinin compounds are short acting drugs
• Monotherapy needs to be extended beyond disappearance of
parasite to prevent recrudescence
• Prevented by combining Artemisinin compounds with other longer
acting drugs
• Indicated by WHO as first line treatment for acute uncomplicated
resistant falciparum malaria
• Advantages
• Rapid clinical & parasitological cure
• High cure rates and low recrudescence rates
• Helps to slow down the emergence of resistance *
• Good tolerability profile
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ACT Regimens in use
• Artemether – Lumefantrine
• Artesunate – Amodiaquine
• Artesunate – Sulfadoxine, pyrimethamine
• Artesunate - Mefloquine
• Dihydroartemisinin (DHA) – Piperaquine
• Artesunate- pyronaridine
• Arterolane – Piperaquine
• Artemisinin - Piperaquine
• Etc

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11. Antibiotics
a. Tetracycline, Doxycycline.
• Slow but potent action on erythrocytic stage of all MP & Pre-
erythrocytic stage of falciparum
• Cannot be used in Children
• Mechanism of Action
• Inhibition of protein synthesis by binding to 30S ribosomal subunit

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Antibiotics….
b. Clindamycin
• Semi-synthetic derivative of Lincomycin (produced by the
actinobacterium Streptomyces lincolnensis)
• Mechanism of Action
• Plasmodial protein synthesis inhibitor by binding
to the 50S ribosomal sub-unit.
• Derived from Lincomycin by using thionyl chloride
to replace the 7-hydroxy group with a chlorine atom
with inversion of chirality
• Usually combined with Quinine/CQ
• May be used as an alternative to the
tetracyclines in Children

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12. Acridines
• Mepacrine
• Unclear mechanism of action
• DNA intercalation
• Interference with mitochondrial electron transport
• Obsolete due to severe side effects
• Toxic psychosis
• Mutagenic & carcinogenic

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 GOODLUCK!

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