ANTIMALARIALS

ANTIMALARIAL
AGENTS
PRESENTED BY:MARIYAM JOUHARA B M
Dept. Of Pharmaceutical chemistry
Contents
 INTRODUCTION
 LIFE CYCLE OF MALARIAL PROTOZOA
 TYPES OF CHEMOTHERAPY
 CHEMICAL CLASSIFICATION OF ANTIMALARIAL AGENTS
 SAR OF SOME IMPORTANT CLASSES:QUINOLINOMETHANOL DERIVATIVES,4-AMINOQUINOLINES,
8-AMINOQUINOLINES
 ARTEMISININES- AN OVERVIEW
INTRODUCTION
ANTIMALARIAL AGENTS: Drugs used for the treatment or prophylaxis of malaria.
MALARIA
 An infectious communicable disease
 CAUSATIVE ORGANISM: Plasmodium falciparum, P. vivax, P. malaria, P. ovale -
subkingdom protozoa
 TRANSMITTED BY: Female anopheles mosquito
 SYMPTOMS: Chill, fever, fatigue, niht sweats, Shivering ,Diarrhoea, nausea, vomiting,
fast heart beat, pallor
LIFE CYCLE OF MALARIAL PTOTOZOA
SEXUAL PHASE-HUMAN
TROPHOZOITES
MEROZOITES ERYTHROCYTES Multiplication stage
Reinfection
Maturation LIVER Cell rupture
Merozoites (symptomatic)
Pre-erythrocytic stage
(Asymptomatic)
GAMETOCYTES
SPOROZOITES
Insect bite
SPOROZOITES
STOMACH TROPHOZOITES
SALIVARY GLAND
ERYTHROCYTES
ASEXUAL PHASE-MOSQUITO
TYPES OF CHEMOTHERAPY
1. TISSUE SCHIZONTICIDES:
 Drugs which eradicate exoerythrocytic liver tissue stage of parasite
 Used to prevent relapse and as prophylactic agent.
 Eg:Primaquine, Pyrimethamine, Chlorguanide.
2. BLOOD SCHIZONTICIDES:
 Drugs which destroy the erythrocytic stage of plasmodium.
 Cures cases of falciparum malaria and suppress relapses.
 Eg:Chloroquine, Amodiaquine, Santoquine, Proguanil, quinine,Mefloquine,
Halofantrine, Pyrimethamine.
TYPES OF CHEMOTHERAPY
3.GAMETOCYTOCIDES
 Agents used to kill the sexual forms of plasmodia (gametocytes)
 Helps to prevent the transmission.
 Eg. Primaquine(for all variant), Chloroquine, Quinine(except for falciparum)
4.SPORONTICIDES
 Drugs which acts against sporozoites and capable of killing these organism as
soon they enter the blood stream.
 Eg. Primaquine, Chlorguanide.
CLASSIFICATION
1. CINCHONA ALKALOIDS
CLASSIFICATION
2. 7-CHLORO-4-AMINO QUINOLINES
3. 8-AMINO QUIONOLINES
CLASSIFICATION
4. ACRIDINE DERIVATIVES
5. ANTIFOLATES
a. BIGUANIDES
CLASSIFICATION
b. DIAMINO PYRIMIDINES
Pyrimethamine Trimethoprim
6. SULPHONAMIDES AND SULPHONES

CLASSIFICATION
7.PHENANTHRENE METHANOL
9. SESQUITERPENE LACTONES
Artemether Artesunate
CLASSIFICATION
9. QUINOLINOMETHANOL DERIVATIVES
Mefloquine, quinine, quinidine
10. ANTIBIOTICS: Tetracyclins, Macrolides, Lincosamides .

11.OTHERS: a. Imidazole-Ketoconazole, miconazole nitrate
b. 1,4-Naphthaquinone-Lapinone, menoctone
GENERAL STRUCTURAL COMPOSITION OF
ANTIMALATIAL AGENT
HETEROCYCLIC RING BINDING GROUP BASIC MOIETY
• BICYCLIC [QUINOLINE] • ALCOHOLIC • TERTIARY AMINE [AMINOQUINOLINES]

• TRICYCLIC[PHENANTHRENE/ACRIDINE] RESIDUE[QUINOLINOMETHANOL DER.] • QUINUCLIDINE NUCLEUS[QUININE]
• AMINO RESIDUE[AMINOQUINOLINE
DER.]
STRUCTURAL ACTIVITY RELATIONSHIP
Quinolinomethanol derivatives
I . Heterocyclic ring :
• quinoline ring
9
5 • Substitution in the ring:
4
6 At C6 : Methoxy gp ( eg. Quinine) is not essential for the activity and can
3
be replaced by a cl- atom without any loss of activity
7 2 At C8: Introduction of halogen or trifluoromethyl gp usually increases the
8
1 activity.(eg. Mefloquine)
At C2 : Blocking of position 2 methyl or CF3 (as in mefloquine) increases
the activity(as it prevent invitro oxidation)
SAR
II. Binding gp
 Binding gp is an alcoholic residue.
9  Modification of the sec. Alcohol at C9 through oxidation, esterification
or similar process diminishes the activity.
III.Basic moiety
 Attached at C9
 Basic moiety can be Quinuclidine nucleus (eg. cinchona alkaloids) or an
alkyl tertiary amine.
 The alkyl tertiary amine is essential for the activity.

SAR
4-Aminoquinolines • Heterocyclic ring - quinoline nucleus
• Binding Gp-Amino residue
• Basic moiety – 30 alkyl amino side chain- optimal for activity
• At C3:methyl gp at C3 reduces the activity Eg: santoqine
5 4
• At C4:The dialkyl amino alkyl side chain with 2-5C atoms
6
3 between 'N' is optimal for activity.
7
2 Eg: Chloroquine
8 1
SAR Modification on the alkyl amino side chain
 Substitution of hydroxyl gp on one of the ethyl gp 3 0 reduces the
toxicity. Eg: Hydroxychloroquine
 Introduction of aromatic ring in the side chain gives compound with
reduced toxicity and activity. Eg: Amodiaquine

SAR
 The introduction of unsaturated bond in the side chain was not
detrimental to the activity.
 The D-isomer of chloroquine is less toxic than L -isomer

SAR
8-AMINO QUINOLINES  Heterocyclic ring - quinoline nucleus
5 4  At C6 –the methoxy gp is essential for the activity.

6
3  At C8 -The dialkyl amino alkyl side chain with 4-6 Carbon
2 side chain is optimal for the activity.

7
8 1
ARTEMISININES
 SOURCE-Artemisia annua
 Chemical nature: sesquiterpene Lactones
 Semisynthetic derivatives: artemether, artesunate, artether
ARTESIMININ ARTEMETHER ARTESUNATE
• Indicated for the intial treatment of severe malaria- acute uncomplicated Plamodium Falciparum
Malaria,Chloroquine- resistant plasmodium,Cerebral malaria.
SAR
 Introduction of a Lipophlic gp ,gives Artemether and

14
4 5 artether which are oil soluble
6
3 7
15 1  Introduction of hydrophilic moiety leads to sodium
2 8
13 12 artesunate ,which is water soluble.
11 9  Both lipophilic and hydrophilic der. Are more active than parent.
10
 1,2,4-trioxane ring is essesntial
 Integriy of 4 rings is required for full antimalarial activity.

MECHANISM OF ACTION(Free radical mechanism)
ARTEMISININ is converted to its active DHA interacts with intra-parasitic Heme- Formation of free radical intermediates,
metabolite DIHYDRO ARTEMISININ iron resulting in the cleavage of which inhibit parasitic nucleic acid &
(DHA) endoperoxide bridge protein synthesis.
Free radicals also alkylate and poison one

Plasmodium gets deprived of essential
or more essential
nutrient ,there by drug inhibit growth
malarial proteins(eg;EXP1, glutathione S-
and kills the plasmodium.
transferase)
REFERENCE
 Text book of Medicinal chemistry-Alagarswamy
 Foye's principles of medicinal chemistry- Thomas L Lemke _et_al
 Essentials of Medicinal chemistry-2nd edition- Andrejus Korolkovas
 Wilson and Gisvold’s Text book of Organic and Medicinal chemistry-12 th edition- John M. Beale et_al
 Pubchem
THANK YOU

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ANTIMALARIAL

6. SULPHONAMIDES AND SULPHONES

10. ANTIBIOTICS: Tetracyclins, Macrolides, Lincosamides .

HETEROCYCLIC RING BINDING GROUP BASIC MOIETY

• BICYCLIC [QUINOLINE] • ALCOHOLIC • TERTIARY AMINE [AMINOQUINOLINES]

 Binding gp is an alcoholic residue.

9  Modification of the sec. Alcohol at C9 through oxidation, esterification

or similar process diminishes the activity.

 Basic moiety can be Quinuclidine nucleus (eg. cinchona alkaloids) or an

alkyl tertiary amine.

 The alkyl tertiary amine is essential for the activity.

 Substitution of hydroxyl gp on one of the ethyl gp 3 0 reduces the

toxicity. Eg: Hydroxychloroquine

 Introduction of aromatic ring in the side chain gives compound with

reduced toxicity and activity. Eg: Amodiaquine

 The introduction of unsaturated bond in the side chain was not

detrimental to the activity.

 The D-isomer of chloroquine is less toxic than L -isomer

5 4  At C6 –the methoxy gp is essential for the activity.

2 side chain is optimal for the activity.

ARTESIMININ ARTEMETHER ARTESUNATE

 Introduction of a Lipophlic gp ,gives Artemether and

 Integriy of 4 rings is required for full antimalarial activity.

Free radicals also alkylate and poison one

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