Biotechnology, Fermentation, Types of Bioreactors.

1. Antimalarial drugs

2.  Malaria is the most important parasitic infection of humans. 1.6 billion
people live in malaria endemic area
 300 million clinical cases per year
 90 % of cases occur in Africa
 2.5-3.5 million deaths per year, mainly in children from 1 - 4 years
Malaria

3.  Malaria is transmitted by the infected female Anopheles mosquito.
 It is caused by four species of plasmodium protozoa. The four plasmodium
species are:
 P. Falciparum and P. vivax (Responsible for Tertian Malaria ).
 P. Malariae and P. ovale (Responsible for Quartan Malaria ).
Causative agents of Malaria

5.  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.
Symptoms of Malaria

6.  Sporozoiticides :-
 These drugs act against sporozoites and are capable of killing these
organisms as soon as they enter the bloodstream after a mosquito bite.
Chemotherapy of Malaria

7.  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.
 This is the easiest phase to treat because drug delivery into the blood
stream can be accomplished rapidly
 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.
Chemotherapy of Malaria

8.  Erythrocytic phase drugs:
 Quinine
 4-Substituted quinoline derivatives:
 4-Aminoquinolines: chloroquine, hydroxychloroquine
 Mefloquine and halofantrine
 Exoerythrocytic phase drugs:
 8-Aminoquinoline derivatives as primaquine
 Antimetabolites:
 Pyrimethamine and proguanil.
 Artemisinins
Antimalarial Agents

9. N
N
C
H
H2C
H3CO
HO
H
H
Quinine
4-quinolinemethanol
Quinuclidine
 Quinine is natural alkaloid isolated extracted from cinchona bark.
 It was the first effective treatment for malaria caused by p. falciparum.
 The major side effects of quinine are cinchonism (skin rashes, deafness,
diminished visual acuity or blindness, anaphylactic shock, and disturbances
in heart rhythm or conduction, and death from cardiotoxicity), myocardial
depression, vasodilatation, hemolytic anemia.
 Quinine can cause premature contractions in the late stages of pregnancy.
Quinine

10.  Mechanism of Action of quinoline derivatives:
 Hemozoin (Malarial pigment) Hypothesis.
 The plasmodium parasite utilizes host hemoglobin as a source of amino
acids producing hemozoin which is toxic to host cells leading to its lysis.
 Quinine and 4-substituted quinolines, form a complex with hemozoin
which is toxic to the erythrocytes and parasites
 Weak Base Hypothesis.
 Since quinine and the 4-substituted quinolines are weak bases so they
accumulate in acidic pH inside the plasmodium resulting in elevating the
pH in the plasmodium
 This reduces the parasite's ability to digest hemoglobin thus reducing the
availability of amino acids.
 Generally, the 4-substituted quinolines disrupt hemoglobin digestion in
sensitive organisms
Quinine

11.  Quinacrine (9-aminoacridine derivative) main effects are as an antiprotozoal
and anthelmintics.
 Quinacrine has weak antimalarial activity.
 Mepacrine is not the drug of choice because side effects are common,
including toxic psychosis.
 The other synthetic antimalarials were derived from it.
Mepacrine or Quinacrine
N Cl
HN
N
CH3
CH3
OH
Hydrochloroquine

12.  Substitution at any position of the quinoline ring decreases the activity.
 The replacement of one of its N-ethyl groups with hydroxyethyl to produce
hydroxychloroquine decreases the activity and reduces the toxicity.
 Chloroquine is effective for cure and as a suppressive prophylactic for
treatment of P. malariae and susceptible P. falciparum.
 Chloroquine is also prescribed for treatment of rheumatoid arthritis.
4-Aminoquinoline Derivatives

13.  Mefloquine:
 Mefloquine is only available in an oral dosage form.
 Mefloquine is an antimalarial agent which acts as a blood schizonticide
(erythrocytic stages). However, the drug has no effect against the
exoerythrocytic (hepatic) stages of the parasite.
 Mefloquine is an effective suppressive prophylactic agent against P.
falciparum.
Other 4-substituted quinoline derivatives

14.  Primaquine is active against exoerythrocytic stages (hepatic stages and
gametocytes) of all strains of plasmodium so prevent transmission.
 Substitution at any position of the quinoline ring decreases the activity.
 Mechanism of Action.
 Primaquine can generate reactive oxygen species via an autoxidation of
the 8-amino group.
 As a result cell destructive oxidants such as hydrogen peroxide,
superoxide and hydroxyl radical can be formed.
8-Aminoquinolines: Primaquine

15.  Lumefantrine.
 Lumefantrine is a fluoren derivative antimalarial drug used only in
combination with artemether.
 The term "co-artemether" is sometimes used to describe this
combination.
Other related derivatives

16.  Pyrimethamine (Daraprim)
 It is a potent inhibitor of dihydrofolate reductase, with about 1000
higher affinity for binding to plasmodium than host enzyme so it
selectively treat plasmodium infections.
 It is a blood schizonticide without effects on the tissue stage of the
disease.
 Combined with sulfadoxine (long acting sulfonamide)[Fansidar®] to
provides sequential block of plasmodium folic acid synthesis for
treatment and prevention of chloroquine-resistant malaria.
Antimetabolites

17.  Artemisinins extracted from Chinese herb Artemisia annua and used as
herbal remedy for fevers and malaria in China and other Asian countries.
 Very rapid-acting
 Well-tolerated, minimal toxicity
 Short half-lives necessitate combination.
 They contain Sesquiterpene lactone with a chemically rare peroxide bridge
linkage which is responsible for the majority of its antimalarial action
 Artemisinin derivatives lacking endoperoxide bridge are devoid of
antimalarial activity.
Artemisinins

18.  Artemisinins cause oxidative damage of the parasite membrane by virtue of
the free radicals.
 Heme/iron mediates breakage of endo-peroxide bridge with the formation of
free radicals or electrophilic intermediates which alkylate protein.
 Artemisinins cause oxidative damage of the parasite membrane by virtue of
the free radicals, SO:
 Antioxidants block antimalarial activity.
 Iron chelators antagonize antiparasitic effect of artemisinin.
Artemisinins

19.  They are gamitocidals (exoerythrocytic stage )and active against
trophozoites (erythrocytic stage).
 Little or no resistance is reported.
 The combinations of antimalarial drugs currently prescribed can be
divided into two categories :
 Artemesinin based combinations: Lumefantrine is an antimalarial
drug used only in combination with artemether.
 Non-artemesinin based combinations: Sulfadoxine-Pyrimethamine and
Chloroquine or quinine
Artemisinins