MalariaMalaria

Malaria

Malaria is transmitted by the infected female Anopheles

mosquito is caused by four species of plasmodium protozoa.

The four plasmodium species are

1) P. falciparum (Malignant Tertian, Subtertian).

2) P.vivax ( Benign Tertian Malaria ).

3) P. Malariae ( Quartan Malaria ).

4) P. ovale (Mild Tertian Malaria).

Malaria

Life cycle of malaria

Infection from plasmodia can cause anemia, pulmonary edema, renal failure, jaundice, shock, cerebral malaria, and if not treated in a timely manner, can result in death.

Types of Chemotherapy

Tissue Schizonticides.

These drugs eradicate the exoerythrocytic liver-tissue

stages of the parasite which prevents the parasite's

entry into the blood.

Drugs of this type are useful for prophylaxis.

Blood Schizonticides.

These drugs destroy the erythrocytic stages of parasites

and can cure cases of falciparum malaria or suppress

relapses..

Types of Chemotherapy

Gametocytocides.

Agents of this type kill the sexual forms of the

plasmodia (gametocytes), which are transmittable to

the Anopheles mosquito, thereby preventing

transmission of the disease.

Sporontocides (sporozooiticides).

These drugs act against sporozoites and are capable of

killing these organisms as soon as they enter the

bloodstream following a mosquito bite.

Treatment of Malaria

2 classes of natural drugs played a role in the development

of synthetic antimalarial drugs:-

4-quinolinemethanol derivatives

The 9-aminoacridines

Treatment of Malaria

4-quinolinemethanol derivatives;

quinine (extracted from cinchona bark) was the first

known antimalarial; its use began in Europe in the 17th

century.

Recently, it has been employed to treat chloroquine

resistant strains of P. falciparum.

N

N

C

HH2C

H3CO

HOH

H

Quinine

Treatment of Malaria

The 9-Aminoacridines

9-aminoacridine it self has antibacterial activity while

quinacrine (a derivative of 9-aminoacridine) posses

weak antimalarial activity.

N

H3CO

Cl

HN

CH3

N

CH3

CH3

Quinacrine

Treatment of Malaria

With the beginning of World War II, a massive effort was

begun to search for synthetic alternatives to quinine and

the development of more effective antimalarial agent than

quinacrine.

This results in the following synthetic antimalarials.

4-aminoquinolones

8-aminoquinolones

Quinoline-4-methanols

Treatment of Malaria

4-aminoquinolones;

chloroquine and hydrochloroquine, are structurally

similar to the right half of quinacrine.

N Cl

HNN

CH3

CH3

CH3

N Cl

HNN

CH3CH3

OH

Chloroquine Hydrochloroquine

Treatment of Malaria

N Cl

HNN

CH3

CH3

CH3

N Cl

HNN

CH3CH3

OH

Chloroquine Hydrochloroquine

N

H3CO

Cl

HN

CH3

N

CH3

CH3

Quinacrine

Structural similarity between quinacrine and 4-aminoquinolines

Treatment of Malaria

8-aminoquinolones;

pamaquine and primaquine, retain the

methoxyquinolone nucleous of quinine and quinacrine

H3CO

HNN

CH3

H3CO

HNNH2

CH3

N N

CH3

CH3

Pamaquine Primaquine

Treatment of Malaria

H3CO

HNN

CH3

H3CO

HNNH2

CH3

N N

CH3

CH3

Pamaquine Primaquine

N

N

C

HH2C

H3CO

HOH

H

Quinine

Structural similarity between quinine and 8-aminoquinolines

Treatment of Malaria

Quinoline-4-methanols;

mefloquine and halofantarine, show similarity to the 4-

quinolonemethanol portion of quinine.

N

HONH

CF3

CF3

Mefloquine

F3CCl

Cl

HO N CH3

CH3

Halofantrine

Treatment of Malaria

N

HONH

CF3

CF3

Mefloquine

F3CCl

Cl

HO N CH3

CH3

Halofantrine

N

N

C

HH2C

H3CO

HOH

H

Quinine

Structural similarity between quinine and quinoline-4-methanol

4-Substituted quinolines

4-Substituted quinolines

This class includes 5-compounds:

Quinine

Chloroquine

Hydroxychloroquine

Mefloquine

Halofantrine

They share structural similarity, have same mechanism of

action and resistance.

They are rapidly acting blood schizonticides with activity

against plasmodium in the erythrocytic stage.

Mechanism of action Weak Base Hypothesis.

The 4-substituted quinolines are weak bases and are

thought to accumulate in a location which is acidic.

Because the extracellular fluid of the parasite is at pH

7.4 the weak base will move toward a more acidic pH.

Once in the lysosome an acid/base reaction occurs

elevating the pH in the lysosome which in turn reduces

the parasite's ability to digest hemoglobin thus reducing

the availability of amino acids.

It is generally believed that the 4-substituted quinolines

disrupt hemoglobin digestion in sensitive organisms

Mechanism of resistance

The development of resistance is thought to be a

spontaneous gene mutation leading to enhanced drug efflux

thus leading to rapid removal of the drug from the organism

and hence reduce the effectiveness of the drugs

Rapid metabolism of the antimalarial by resistant strains.

It has been shown that cyctochrome P-450 activity parallels

increased resistant to specific drugs

Therapeutic Application They rapidly acting blood schizonticides with activity

against plasmodium in the erythrocytic stage.

The drug of choice for treatment of malaria caused by

Plasmodium falcipamm, P. ovale, P. vivax, and P. malariae

in regions infected by chloroquine-resistant P. falciparum is

quinine with mefloquine and halofantrine as alternative

treatment agents.

The 4-substituted quinolines, depending on the specific drug

in question, may also be used for prophylaxis of malaria.

Two types of prophylaxis are possible, causal pro phylaxis

(prevents the establishment of hepatic forms of the

parasite) and suppressive prophylaxis (eradicates the

erythrocytic parasites but has no effect on the hepatic

forms)

Quinine

N

N

C

HH2C

H3CO

HOH

H

Quinine is the most prevalent alkaloid present in the bark extracts (about 5%) of cinchona.

Structure activity relationship:- Four stereo-chemical centers exist in the molecule (at C-

3, C-4, C-8, and C-9) Quinine, absolute configuration of 3R:4S: 8S:9R, and

Quinidine, absolute configuration of 3R:4S: 8R:9S, and their optical isomers all have antimalarial activity while their C-9 epimers are inactive.

Quinine

N

N

C

HH2C

H3CO

HOH

H

Modification of the secondary alcohol at C-9, through

oxidation, esterification, or similar processes, diminishes

activity.

The quinuclidine portion is not necessary for activity;

however, an alkyl tertiary amine at C-9 is important.

Chloroquine (Aralen)

Structure-activity relationships:-

Chloro at the eight position increased activity while

alkylation at C-3 and C-8 diminished activity.

The replacement of one of its N-Ethyl groups with

hydroxyethyl produced hydroxychloroquin, a compound

with reduced toxicity.

N Cl

HNN

CH3

CH3

CH3

Chloroquine

Chloroquine (Aralen)

It is commonly administered as the racemic mixture.

It is an excellent suppressive agent for treating acute attacks of malaria caused by P. vivax and P. ovale and is effective for cure and as a suppressive prophylactic for treatment of P. malariae and susceptible P. falciparum.

It is for treatment of rheumatoid arthritis, discoid lupus erythematosus and photosensitivity diseases

N Cl

HNN

CH3

CH3

CH3

Chloroquine

Mefloquine (Lariam)

Mefloquine is only available in an oral dosage form.

Mefloquine is an effective suppressive prophylactic agent

against P. falciparum.

The drug also has high efficacy against falciparum malaria

with a low incidence of re crudescence.

The drug is in effective against sexual forms of the

organism

N

COOH

CF3

CF3N

HONH

CF3

CF3

Mefloquine

Metabolism

Mefloquine (Lariam)

The side effects:

neuropsychiatric, gastrointestinal (nausea, vomiting,

and diarrhea), dermatologic (rash, pruritus, and

urticaria), and cardiovascular (bradycardia, arrhythmias,

and extrasystoles).

N

COOH

CF3

CF3N

HONH

CF3

CF3

Mefloquine

Metabolism

Halofantrine (Hafan)

It is an alternative drug for treatment of both chloroquine-

sensitive and chloroquine-resistant P. falciparum malaria.

The drug is metabolized via N-dealkylation to the

desbutylhalofantrine which is several times more active

than the administered drug

F3CCl

Cl

HO N CH3

CH3

Halofantrine

F3CCl

Cl

HO NHCH3

Desbutylhalofantrine

Metabolism

8-Aminoquinolines

Pamaquine and Primaquine H3CO

HNNH2

CH3

N

Primaquine

H3CO

HNN

CH3

N

CH3

CH3

Pamaquine

Pamaquine was first introduced for treatment of malaria in

1926 and has been replaced with primaquine.

Primaquine is active against latent tissue forms of P. vivax

and P. ovale and is active against the hepatic stages of P.

falciparum.

The drug is not active against erythrocytic stages of the

parasite, but does possess gametocidal activity against all

strains of plasmodium.

Pamaquine and Primaquine

Primaquine is the drug of choice for treatment of relapsing vivax

and ovale forms of malaria and will produce a radical cure of the

condition.

It is recommended to be combined with chloroquine to eradicate

the erythrocytic stages of malaria.

Primaquine is not given for long-term treatment because of

potential toxicity and sensitization (especially with patients have

glucose-6-phosphate dehydrogenase deficiency, In these cases

hemolytic anemia may develop).

H3CO

HN COOH

CH3

NPrimaquine

H3CO

HNNHCOCH3

CH3

N

N-Acetylprimaquine

+

Carboxyprimaquine

Metabolism

Pyrimethamine

Pyrimethamine

N

N

H2N

NH2

Cl

CH3

Pyrimethamine

H2N S

Sulfadoxine

HN

O

O

N

N

H3CO OCH3

Pyrimethamine (Daraprim) is a potent inhibitor of dihydrofolate reductase

It has a significantly higher affinity for binding to the dihydrofolate reductase of plasmodium than host enzyme and as a result has been used to selectively treat plasmodium infections.

Combined with sulfadoxine (long acting sulfonamide) and quinine for treatment and prevention of chloroquine-resistant malaria (Plasmodium faldparum, P. ovale, P. vivax, and P. malaria).

Pyrimethamine is a blood schizonticide without effects on the tissue stage of the disease

Atovaquone-proguanil

Atovaquone was originally developed as an antimalarial, but

because of the high failure rate (30%), it is not prescribed

as a single chemical entity but, rather, is used to treat

pneumocystis

OH

O

O

Cl

Atovaquone

Atovaquone-proguanil

alovaquone has been combined with proquanil as an

effective prophylactic and therapeutic antimalarial

The two drug together (Malarone) exhibit synergy in which

proguanil reduces the effective concentration of atovaquone

needed to damage the mitochondrial membrane and

atovaquone increases the effectiveness of proguanil.

HN

HN

HN

NH NHCl

Proquanil

N N

NH2Cl

NH2

Cycloguanil(Active)

Metabolism

Artemisinins

O

O

CH3H

H

H3C

CH3

H

O

O

OArtemisinin

O

O

CH3H

H

H3C

CH3

H

O

O

OCH3

Artemether (Artenam)

O

O

CH3H

H

H3C

CH3

H

O

O

O

Artesunate

HO

O

O

F3C

CF3 CH3

O

O

CH3

O

H

Arteflene

Artemisinins

Mechanism of Action.

The artemisinins appear to kill the parasite by a free

radical mechanism producing oxidative damage to

the parasites membrane.

These compounds have gametocytocidal activity as well as

being active against late stage parasites and trophozoites