Antimalarial Drugs

Prof. Rushikesh G. Diware

Introduction
• endemic in most parts of India and other tropical countries

• most widespread diseases, is caused by an Plasmodium parasite

• transmitted to humans by the Anopheles mosquito.

• It infects several hundred million people each year, results in several million
deaths annually

• complex disease to treat.

• The causative agent is a group of parasitical protozoa of the Plasmodium genus

transmitted by the female Anopheles mosquito.
Cont….
• treatment : quinine sulphate

• One of the most effective preventions is controlling the mosquito population that
is the vector carrying the parasite to humans.

• The human immune system does respond to the parasite,

• Sequencing the plasmodium genome is providing information that may lead to

other approaches to prevent and treat this debilitating disease.
• As per latest WHO estimate.* ~ 216 million cases and ~ 0.445 million deaths
occurred globally due to malaria in 2016
• 90% cases and deaths were in Africa and 7% in south-east Asia (including India).
NMEP, NAMP and NVBDCP
• In India the National Malaria Eradication Programme (NMEP) started in 1958,

• achieved near complete disappearance of the disease in 1960s (from 75 million cases in 1950s to 0.1 million

cases in the 1960s).

• due to the development of insecticide resistance among mosquitoes and other factors, it staged a comeback in

the mid 1970s (6.47 million cases in 1976), and continues to prevail in endemic/ subendemic proportions,

• so that 80% indian population lives in malaria risk areas.

• The NMEP was renamed National Antimalaria Programme (NAMP), which now is

• ‘National vector borne diseases control programme’ (NVBDCP) with a wider disease coverage.

• For the year 2016, the NVBDCP has reported 1.06 million confirmed malaria cases in India, out of which

nearly 50% were falciparum malaria with 242 recorded deaths

History
• Malaria’s name is derived from “mala aria” or bad air

• has been called ague, intermittent fever, marsh fever, and The Fever

• The name is based on the early knowledge that malaria was associated with swamps and badly
drained areas.

• The use of quinine for treating malaria has been known since the 17th century.

• The Anopheles gambiae mosquito uses still water that sits in ponds and containers to breed.

• The gathering of humans in farming communities provided the necessary concentration of people
to form a reservoir of hosts for the parasite and “food” for the mosquitoes breeding in the ponds
Cont…
• Anopheles mosquito is the carrier of the causative protozoa was
obtained by Dr. Ronald Ross
• recognized in 1902 by receipt of the Nobel Prize in Medicine
• parasite was carried in the stomach and salivary glands of the
Anopheles mosquito suggested by Dr. Ross
• Malaria is caused by four species of the one-cell protozoan of the
Plasmodium genus. They are:
• Plasmodium falciparum Plasmodium vivax:
• Plasmodium malariae Plasmodium ovale:
potential ways to control malaria
• Elimination of the vector
• Drug therapy
• Vaccination.
• malaria has been eliminated from North America, Europe, and parts of
Asia
• The current antimalarial drugs, although reasonably effective,
• Have significant adverse reactions, and resistance is increasing
Malaria: Causing parasite
• caused by four species of the one-cell protozoan of the Plasmodium genus
1. Plasmodium falciparum: cause approximately 50% of all malaria.

• It causes the most severe form of the disease

• patients feel ill between acute attacks, debilitating form of the disease.

• One of the reasons it leaves the patient so weak is because it infects up to 65% of the patient’s
erythrocytes.

2. Plasmodium vivax: second most species causing about 40% of all malarial

• It can be very chronic in recurrence because it can reinfect liver cells.

3. Plasmodium malariae: Although causing only 10% of all malarial cases, relapses are very common.

4. Plasmodium ovale: This species is least common.

• Stage-I: No drug is effective in this stage.
• Stage-II: Primaquine and pyrimethamine can block at this stage.
• Stage-III: Primaquine can only prevent because fever occurs at this stage.
• Stage-IV: Chloroquine, amodiaquine, santoquine, proguanil.
• Stage-V: Primaquine only.
  Etiology of Malaria (malaria Cycle)

• The mosquito stores the sporozoite form of the protozoan in its salivary glands.

• Upon biting the patient, the sporozoites are injected into the patient’s blood.

• Within minutes after being injected into the patient’s blood, the sporozoites begin entering hepatocytes

where they become primary schizonts and then merozoites.

• At this point, there are no symptoms.

• Depending on the Plasmodium species, the merozoites either rupture the infected hepatocytes and enter

systemic circulation or infect other liver cells.

• The latter process is seen with P. vivax, P. malariae, and P. ovale, but not P. falciparum, and produces

secondary schizonts
 Cont…
• This secondary infection of the liver can be very damaging and is one of the sites for possible drug
intervention.

• Killing the secondary schizonts would accomplish two things, protect the liver from further damage and
eliminate reservoir of schizonts that can change to merozoites and enter systemic circulation.

• protozoan changes from sporozoite to schizont to merozoites, its immunological character changes.

• each form of the parasite produces a different set of proteins.

• At the same time, once the merozoites have left the hepatocyte and are in systemic circulation, they are
susceptible to attack by the patient’s immune system provided that it has “learned” to recognize the
parasite.
 Cont…
• Merozoites in systemic circulation now infect the patient’s erythrocytes where they reside for 3 to 4 days before reproducing.

• The reproduction stage in the erythrocyte can either produce more merozoites or another form called gametocytes.

• The latter has different immunological properties

• newly formed merozoites or gametocytes burst out of the infected erythrocytes.

• The new merozoites infect additional erythrocytes and continue the cycle of reproducing, bursting out of the erythrocytes,

and infecting more erythrocytes.

• The debris from the destroyed erythrocytes is one of the causes of severe fever and chills.

• patient’s immune system will respond with repeated exposure to the parasite, and this will contribute to the patient’s

discomfort
Cont..

• The conversion of merozoites results in male and female gametocytes

• After entering the mosquito, they “mate,” producing zygotes in the

mosquito’s stomach.

• in the mosquito’s stomach endothelium oocysts.

• they migrate as sporozoites to the mosquito’s salivary gland where the

cycle begins again when the mosquito bites a human.
Classifications
1. Quinolines Alkaloids : Quinine Sulphate, Chinchonidine

1. 4 Amino Quinolines: Chloroquine, Hydroxychloroquine, Amodiaquine, Mefloquine,

Sontoquine

2. 8 amino Quinolines: Primaquine, Pamaquine, Pentaquine, isopentaquine

3. Polycycline antimalerial Agents: Quinacrine, Halfentrine, Pyronaridine, Lumefantrine,

Doxycycline

4. Biguanides and dihydro triazines: Cycloguanil pamoate, Proguanil

5. Miscellaneous : Artesunete, Pyrimethamine, Artemether,

Controlling the Vector, the Anopheles Mosquito

• The Anopheles mosquito has adapted very well to human habitats.

• it requires still water to lay its eggs, wait for them to hatch, and then let the larvae,
who feed on microscopic organisms in the still water, mature.

• Transient still water is ideal because it likely is not going to contain predators that
will feed on the eggs and larvae.

• mosquitoes need 1 to 2 weeks to develop into mature insects.

• This usually is enough time before predators begin to populate the still water.
Cont…
• Two ways to control the mosquito carrier.

• One is to prevent contact between humans and the insect.

• Putting screens on windows and using mosquito netting in bedrooms are very effective.

• Second, elimination of the Anopheles mosquito, usually by application of insecticide and destroying its breeding areas

• Areas that have been successful at eliminating infected mosquitoes include North America, Europe, and Russia.

• To do this, the adult female mosquito must be killed and breeding areas (still water) must be drained.

• One of the most effective insecticides has been dichlorodiphenyltrichloroethane (DDT).

• Dr. Paul Muller received the 1948 Nobel Prize in Medicine for discovering that DDT kills the malaria-carrying Anopheles mosquito.

DDT is very long lasting and, unfortunately, accumulates in the environment.

• Although being long lasting is beneficial from the standpoint of mosquito control, it also means that these insecticides get into the food

chain and can affect both animals, including birds, and humans. Indeed, use of DDT has been banned in most economically developed

countries.
I. Cinchona alkaloids

• The cinchona tree produces four alkaloids

• These alkaloids are the enantiomeric pair

• quinine and Quinidine and their desmethoxy analogs, cinchonidine

(for quinine) and cinchonine (for quinidine).

• Their numbering system is based on rubane.

• The stereochemistry differs at positions 8 and 9 with quinine and

cinchonidine being S,R and quinidine (cinchonine) being R,S.

• Historically, quinine has been the main treatment for malaria until

the advent of World War II when battle in areas where malaria was

endemic led to the search for more effective agents.

Quinine and Quinidine
• Quinine has been used for “fevers” in South America since the 1600s.

• The pure alkaloids, quinine, and cinchonine were isolated in 1820.

• The stereoisomer, quinidine, is a more potent antimalarial, but it is also more toxic (less
selectively toxic).

• Quinine is lethal for all Plasmodium schizonts (site 2) and the gametocites (site 4) from P. vivax
and P. malariae, but not for P. falciparum.

• Today, quinine’s spectrum of activity is considered too narrow for prophylactic use relative to
the synthetic agents
• Quinine is still indicated for malaria caused by P. falciparum resistant to other agents
including chloroquine.

• Many times it is administered in combination with pyrimethamine and sulfadoxine,

doxycycline, or mefloquine depending the specific form of malaria and geographical
location.

• A toxic syndrome is referred to as cinchonism. Symptoms start with tinnitus (hearing noises
without outside source) , headache, nausea, and disturbed vision.

• Cinchonism can proceed to involvement of the gastrointestinal tract, nervous and

cardiovascular system, and the skin.
• used for nocturnal leg cramps,
• The stereoisomer, quinidine, is a schizonticide, but its primary indication is cardiac
arrhythmias.
4-Aminoquinolines
• The 4-aminoquinolines are the closest of the antimalarials

• that are based on the quinine structure.

• This group is substituted at the same position 4 as quinine

• have an asymmetric carbon equivalent to quinine’s C-9 position.

• both isomers are active and the 4- aminoquinoline racemic mixtures are used (mefloquine, only
the R,S-isomer is marketed)

• Replacing the 6-methoxy on quinine with a 7-chloro substituent on three of the 4-aminoquinolines
on cinchona alkaoids
Chloroquine and Chloroquine Phosphate
• Considered the prototypical structure

• came into use in the mid-1940s.

• The phosphate salt is used in oral dosage forms (tablets), and the hydrochloride salt is
administered parenterally.

• chloroquine has been the main antimalarial drug used for both prophylaxis and treatment.

• It is indicated for P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum.

• Chloroquine belongs to the 4-aminoquinoline series of which hundreds have been evaluated,
but only about three to four are still in use.
Mechanism of action
• mechanism of action is still not known.

• Its main site of action appears to be the parasite involving the erythrocyte’s lysosome.

• A very complex mechanism is based on ferriprotoporphyrin IX, which is released by

Plasmodium containing erythrocytes, acting as a chloroquine receptor

• The combination of ferriprotoporphyrin IX and chloroquine causes lysis of the parasite’s and/or

the erythrocyte’s membrane.

• chloroquine may interfere with Plasmodium’s ability to digest the erythrocyte hemoglobin or

the parasite’s nucleoprotein synthesis.

• Drug entering the erythrocyte’s lysosome, which has an acid environment, where it becomes protonated.

• The protonated (positively charged) chloroquine is now trapped inside the lysosome because the pore
that leads out of the lysosome is also positively charged.

• This leaves chloroquine bound to the patient’s hemoglobin preventing the parasite from processing it
properly

• Chloroquine and the other 4-aminoquinolines are not effective against exoerythocytic parasites.

• each of the mechanisms require that the parasite be inside the erythrocyte.

• Chloroquine does not prevent relapses of P. vivax or P. ovale malaria.

• The drug is also indicated for the treatment of extraintestinal amebiasis.

• Effective such as chloroquine has been, it is a poor

• ADR: Adverse reactions include retinopathy, hemolysis in patients with glucose-
6-phosphate dehydrogenase deficiency, muscular weakness, exacerbation of
psoriasis and porphyria, and impaired liver function.

• rheumatoid arthritis, systemic and discoid lupus erythemaosis (possibly as a

immunosuppressant),

• and various dermatological conditions

• Plasmodium gene that confers resistance appears to be the pfcrt gene that codes
for a transporter protein

• Use: Forms of hypercalcemia, Discoid and systemic lupus erythematosus

Hydroxychloroquine.

• In most ways, hydroxychloroquine parallels chloroquine.

• Structurally, it differs solely with a hydroxy moiety on one of the N-ethyl groups.

• it remains in the body for over a month, and prophylactic dosing is once weekly.

• The other indications, both FDA approved and off-label, are very similar.
Amodiaquine.

• Amodiaquine is no longer marketed in the United States, but it is available in Africa.

• When used for prophylaxis of malaria, it had a higher incidence

• of hepatitis and agranulocytosis than that was chloroquine.

• There is evidence that the hydroquinone amine system readily oxidizes to a quinone

imine either autoxidatively and/or metabolically, and this product may contribute to

amodiaquine’s toxicity.
Mefloquine HCl.
• The newest of the 4-aminoquinolines,

• mefloquine, is marketed as the R,S-isomer.

• It was developed in the 1960s as part of the U.S. Army’s Walter Reed Institute for Medical
Research antimalarial research program.

• It differs from the other agents by having two trifluromethyl moieties at positions 2 and 8
and no electronegative substituents at either

• positions 6 (quinine) or 7 (chloroquine).

• being a schizonticide acting before the parasite can enter the erythrocyte.
• raising the pH in the parasite’s vesicles interfering with its ability to process heme

• Mefloquine-resistant strains of P. falciparum have appeared.

• Relapse can occur with acute P. vivax that has been treated with mefloquine because
the drug does not eliminate the hepatic phase of this species, which can reinfect the
liver

• teratogenic in rats, mice, and rabbits

• drug can cause exacerbate mental disorders and is contraindicated in patients with
active depression, a recent history of depression, generalized anxiety disorder,
psychosis, schizophrenia, and other major psychiatric disorders or a history of
convulsions
 8-Aminoquinolines
• The first compound introduced in this series was pamaquine.

• During World War II, pentaquine,isopentaquine, and primaquine became available.

• Only primaquine, after being used during the Korean war, is in use today. All of the 8-aminoquinolines can cause

hemolytic anemia in erythrocytic glucose-6-phosphate dehydrogenase- deficient patients.

• The four agents have a 6-methoxy moiety same as quinine, but the substituents are on the quinoline are located at

position 8

• All agents in this series have a four to five carbon alkyl linkage or bridge between the two nitrogens.

• With the exception of pentaquine, the other three 8-aminoquinolines have one asymmetric carbon.

• Although some differences may be seen in the metabolism of each stereoisomer and type of adverse response, there

is little difference in antimalarial activity based on the compounds stereochemistry.

Primaquine.
• only 8-aminoquinoline currently in use for the treatment of malaria.

• It is not use for prophylaxis. Its spectrum of activity is one of the narrowest of the currently used antimalarial drugs being

indicated

• only for exoerythrocytic P. vivax malaria (site 2) . To treat endoerythrocytic P. vivax, chloroquine or a drug indicated for

• chloroquine-resistant P. vivax is used with primaquine.

• it is also active against the exoerythrocytic stages of P. ovale and primary exoerythrocytic stages of P. falciparum.

• Primaquine also inhibits the gameocyte stage (site 4) that eliminates the form required to infect the mosquito carrier.

• the stereochemistry at the asymmetric is not important for antimalarial activity.

• There appears to be less toxicity with the levorotatory isomer, but this is dose dependent may not be that important at the

doses used to treat exoerythrocytic P. vivax malaria.

 Polycyclic Antimalarial Drugs

• There are three antimalarial drugs that have, in

common, polycyclic ring systems

• The first is the common tetracycline antibiotic,

doxycycline.

• The second is halofantrine, and the third is the

discontinued agent that was used in the South
Pacific, quinacrine.
Doxycycline

• inhibits the pathogen’s protein synthesis by reversibly inhibiting the 30S ribosomal subunit.

• use for malaria is limited to prophylaxis against strains of P. falciparum resistant to chloroquine

and sulfadoxine–pyrimethamine.

• This use normally should not exceed 4 months.

• Because the tetracyclines chelate calcium,

• Interfere with development of the permanent teeth in children. Therefore, their use in children

definitely should be short term

Halofantrine.
• differs from all other antimalarial drugs.

• Halofantrine is a schizonticide (sites 1 and 2) and has no affect on the sporozoite,

gametocyte, or hepatic stages.

• Both the parent compound and N desbutyl metabolite are equally active in vitro.

• specific mechanism of action against the parasite is not known.

• There is contradictory evidence that its mechanism ranges from requiring heme to disrupting
the mitochondria.

• There is a prominent warning that halfantrine can affect nerve conduction in cardiac tissue.
Quinacrine HCl.
• It can be considered one of the most toxic of the antimalarial drugs
even though, at one time, it was commonly used.
• It acts at many sites within the cell including intercalation of DNA
strands, succinic dehydrogenase and mitochondrial electron transport,
and cholinesterase
• It may be tumorgenic and mutagenic and has been used as a sclerosing
agent.
• Because it is an acridine dye, quinacrine can cause yellow
discoloration of the skin and urine.
Biguanides

• Mode of action: Biguanides inhibit dihydrofolate reductase enzyme

and interfere in the folic acid metabolism.
• This leads to inhibition of the nuclear division in malarial parasites.
Proguanil and Cycloguanil

• Atovaquone and proguanil HCl are administered in combination

• the ratio of 2.5 atovaquone to 1 proguanil HCl measured in mg

• Proguanil, developed in 1945, is an early example of a prodrug.

• It is metabolized to cycloguanil by CYP2C19

• Atovaquone is a selective inhibitor of the Plasmodium’s mitochondrial electron

transport system, and cycloguanil is a dihydrofolate reductase inhibitor.
• The combination is effective against both erythrocytic and exoerythrocytic

Plasmodium.

• This drug combination is indicated for malaria resistant to chloroquine, halofantrine,

mefloquine, and amodiaquine.

• Its main site is the sporozoite stage (site 1)

• Its elimination half-life (48–72 hour) is much shorter than the other antimalarial

dihydrofolate reductase
Sulfadoxine and
Pyrimethamine
• The combination is considered to a schizontocid
(site 2).
• The sulfonamide, sulfadoxine, interferes with the
parasite’s ability to synthesize folic acid,
• the pyrimidinediamine, pyrimethamine, inhibits
the reduction of folic acid to its active
tetrahydrofolate coenzyme form.
• warnings of severe to fatal occurrences of
erythema multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis, and serum-sickness
syndromes attributed to the sulfadoxine.
 Atovaquone and Proguanil HCl.

• administered in combination in the ratio of 2.5 atovaquone to 1

proguanil HCl measured in mg (not mmoles).

• Proguanil, developed in 1945, is an early example of a prodrug. It

is metabolized to cycloguanil primarily by CYP2C19.

• The polymorphic nature of this hepatic enzyme explains why

certain subpopulations do not respond to proguanil.

• These groups cannot convert proguanil to the active cycloguanil.

• the combination is active against all the asexual erythocytic forms.
• It has no activity against the sexual gametocyte form.
• The fixed combination contains 500-mg sulfadoxine and 25-mg
pyrimethamine
• wide number of sulfonamides that could be used in combination with
pyrimethamine.
Artemisinin

• newest of the antimalarial drugs

• structurally unique when compared
• parent compound, artemisinin, is a natural product
• Extracted from the dry leaves of Artemisia Annua (sweet wormwood).
• Drugs are mainly artimesinin, Artemether, Artesunate
• Chemically are “trioxane” consisting of the endoperoxide and
dioxepin oxygens
Synthesis of Chloroquine