Synthesis of dihydroartemisinin derivatives as potential antimalarial agents

Mrinal Singha M.S. (PHARM.) Department of Medicinal Chemistry (NIPER)

Introduction Review of literature Traditional antimalarial drugs New antimalarial drugs Limitations of currently used drugs Endoperoxides Background of project Objective of project Work plan Work done Future plans
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Contents

Introduction Malaria
More than 150 Plasmodium species are known Mainly four species infect humans: P. falciparum, P. vivax, P. ovale, P. malariae Malaria parasite is transmitted to female Anopheles mosquitoes from an infected individual when it takes a blood meal as a prelude to the reproductive process

(J. Med. Res. 1996, 103, 26-45.)

Distribution of Malaria
One of the WORLDS LEADING KILLER DISEASE

Currently it affects more than 60% of worlds population Prevalence of malaria parasite depends mainly on climatic factors such as temperature, humidity and rainfalls Malaria is more in tropical and subtropical areas The highest death rate by malaria is found in Africa and south of the Sahara(> 80% death of worldwide)
(Nature 2002, 415, 680-685.) (http://www.cdc.gov/malaria/distributin_epi/index.htm)

Review of literature Traditional antimalarial drugs

1. 8-Aminoquinolines gametocidal in nature Primaquine, Tafenoquine 2. 4-Aminoquinolines are most successful drug both in treatment and prophylaxis accumulate within the acidic food vacuoles of the parasite and kill them Chloroquine, Amodiaquine 3. Quinoline-methanols are drug of choice for relapse cases bind to parasite membrane and causes morphological changes in the food vacuoles of the parasite Quinoline, Mefloquine
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(Antimicrob. Agents Chemother. 1999, 43, 1525-1527.)

Contd.
4. Other

amine derivatives Halofantine and Pyronaridine

5. Dihydrofolate reductase (DHFR) inhibitors Pyremethamine and Proguanil 6. Dihydropteroate synthase (DHPS) inhibitors sulfones and sulfonamides like Sulfadoxine and Dapson

New antimalarial drugs in clinical use and in drug development

Lumifantrine-Artemether (riamet or co-artemether) for treatment of uncomplicated P. falciparum malaria Atovaquone-Proguanil (Malarone) for treatment and prophylaxis of uncomplicated P. falciparum malaria Chlorproguanil-Dapsone (Lap-dap) is currently under development as a replacement for sulfadoxinepyremethamine Fosmidomycin-Clindamycin is for uncomplicated P. falciparum malaria

(Angew. Chem. Int. Ed. 2003, 42, 5274-5293.)

Limitations of tradiationalnitrogen containing drugs

Resistance Primaquine has short half-life and not compatible to patients with glucose-6-phosphate dehydrogenase deficiency Fancidar (Pyremethamine + Sulphadoxine ) has severe cutaneous reaction (Stevenes-Johnson Syndrome) Fancidar is ineffective against P. vivax and carries a significant risk of mortality Mefloquine & Halofantrine are expensive Halofantrine has also cardiotoxicity
(http://www.who.int/emc)
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Endoperoxides
The first-generation endoperoxides include artemisinin (sesquiterpene lactone) and its several semisynthetic derivatives e.g. Water-soluble derivatives ( artesunate and artelinate ) e.g. Oil-soluble derivatives ( artemether and arteether ) Advantages
4 14 3 15 5 15 4 7 14 3 5

H
5a

H
5a

6 7

1.Little or no cross-resistance with other2 antimalarial drugs 2 O 8 O 8a 8a 2.Clear the parasites from peripheral blood more8 rapidly than 12 12 H H over available drugs O 10 9 16 O 10 9 16 3.Resistance to the endoperoxides have not yet developed
O O O

Disadvantages

Artemisinin

Short half-life & poor oral bioavailability

OR Dihydroartemisinin (R = H) Artemether (R = CH3) Arteether (R = CH2CH 3) Sodium Artesunate [R = OCO(CH 2)CO2Na] Sodium Artelinate (R = COONa )

(Antimicrob. Agents Chemother 1999, 43, 1525-1527.)

Mechanism of action of artemisinin

It is toxic to parasites at nanomolar concentration, whereas micromolar concentration is required for toxicity to mammalian cells It causes structural changes in the erythrocyte stage of parasite by affecting the membranes surrounding the food vacuole, nucleus, mitochrondia, endoplasmic reticulum and nucleoplasm

(Bioorg. Med. Chem. 2000, 8, 2739-2745.) (Chem. Pharma. Bull 2001, 49, 1541-1546.) (J. Med. Chem. 1997, 40, 633-638.)
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Contd. Biochemical action of artemisinin depends on two sequential steps- activation & alkylation

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Background of project
H O H O H S

H O H O H OH
O H O

O R

O O R

Artemisinin derivatives with S-linkage

Dihydroartemisinin

Artemisinin derivatives with O-linkage

Cytochrome P-450 enzyme present in liver

Cytochrome P-450 enzyme present in liver

(Korean J. Parasitol. 2005, 43, 123-126.) (Bioorg. Med. Chem. 2004, 12, 3783-3790.)

Neurotoxic & has low half-life

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Contd. Some sulfur-linked derivatives of artemisinin had been made from our laboratory previously and out of which two compounds have shown good antimalarial activity even at concentration lesser than artemisinin These two compounds (1 & 2) are active at dose 50 mg/Kg/day so far whereas artemisinin is active at 100 mg/Kg/day
H O H O H S (1)
(Bhalara., H.;M. S. Thesis,NIPER, Mohali, 2006.)

H O H O H S (2)
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Objective of project
We mainly want to synthesize sulfur containing compounds at C-10

H O H O H S R = e.g. alkyl / substituted alkyl group aryl / substituted aryl group

O R

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Work plan
H O H O H O
H O H O H
H O H S

O H

O H OH

O H

O H O O

O H

O S R O O

O R

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Proposed mechanism of reaction

ice ic t erStnr aece S r a dc n r H nd in Hi
Me O Me O O I I O
RSH

Me O SR

?
Me O SR
isa t ion

Me O O O I I

Me O SR Me O

SR

Me O I RSH

Ano mer

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