Transcript 4-Antimalarial drugs..

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.
Treatment of Malaria
 The 9-Aminoacridines
 9-aminoacridine it self has antibacterial activity
while quinacrine (a derivative of 9-aminoacridine)
posses weak antimalarial activity.
Cl
N
Acridines
Quinacrine
6-Chloro-9-[[4-(diethylamino)-1-methylbutyl]amino]-2methoxyacridine
OCH3
HN
N(C2H5)2
CH3
Synthesis
Cl
H2N
Cl
H
N
Cl
Cyclization
SOCl2
+
OH
OCH3
COOH
OCH3
O
Cl
N
Cl
CH3
H2N
N
N(C2H5)2
OCH3
OCH3
Cl
HN
N(C2H5)2
CH3
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.
Treatment of Malaria
Treatment of Malaria
 8-aminoquinolones;
 pamaquine
and
methoxyquinolone
quinacrine
primaquine,
nucleous
of
retain
the
quinine
and
Treatment of Malaria
Treatment of Malaria
 Quinoline-4-methanols;
 mefloquine and halofantarine, show similarity to
the 4-quinolonemethanol portion of quinine.
Treatment of Malaria
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 prophylaxis (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
 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
 Modification
through
of
the
oxidation,
secondary
alcohol
esterification,
or
at
C-9,
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,
compound with reduced toxicity.
a
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
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 recrudescence.
 The drug is in effective against sexual forms of the
organism
CH3
Chloroquine
7-Chloro-4-(4-diethylamino-1-methylbutylamino)quinoline
HN
N(C2H5)2
Cl
Synthesis
O
Na+HC-
O
CH3
Cl
O
N(C2H5)2
OC2H5
N(C2H5)2
H3C
O
OC2H5
Hydrolysis and
decarboxylation
O
O
O
O
H3C
O
HCl
O
Cl
H3C
HN(C2H5)2
H3C
N(C2H5)2
Chloroquine/ Continued/....
7-Chloro-4-(4-diethylamino-1-methylbutylamino)quinoline
CH3
Cl
HN
Reduction in
presence of
NH3
NH2
H3C
N(C2H5)2 Cl
Cl
N(C2H5)2
Mefloquine (Lariam)
 The side effects:
 neuropsychiatric,
vomiting,
pruritus,
and
and
gastrointestinal
(nausea,
diarrhea),
dermatologic
urticaria),
and
(rash,
cardiovascular
(bradycardia, arrhythmias, and extrasystoles).
Halofantrine (Hafan)
 It
is
an
alternative
chloroquine-sensitive
drug
and
for
treatment
of
both
chloroquine-resistant
P.
falciparum malaria.
 The drug is metabolized via N-dealkylation to the
desbutylhalofantrine
which
is
active than the administered drug
several
times
more
8-Aminoquinolines
Pamaquine and Primaquine
 Pamaquine
malaria
in
was
first
1926
introduced
and
has
for
been
treatment
replaced
of
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).
Pyrimethamine
Pyrimethamine
 Pyrimethamine
(Daraprim)
dihydrofolate reductase
is
a
potent
inhibitor
of
 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
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.
Artemisinins
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