Content: Introduction History Chemistry of artemisinin Structural activity relationship of artemisinin Mechanism of action Drug interactions Malaria is a very common disease. This probably originated in Africa around 30 million years ago.  In 1600s first treatment to malaria was recorded in Peru where native tribes used bitter bark of cinchona, to reduce the fever and pain. In 1897 Sir Ronald Ross described female anopheles mosquito as the vector of the disease. In 1950s the disease rebounded largely due to emergence of parasites resistant to drugs like chloroquine. In 1967 a plant screening research program code named “Project 523” was set up in China by the People’s liberation army ordered by Mao Zedong at the request of North Vietnamese. Under able leadership of Dr. Y. Tu more than 2000 herbs preparations were investigated . Out of which 640 herbs were hits. The turning point came when Sweet wormwood extract showed a promising degree of inhibition in mouse model. Although the progress was not smooth as the observation was not reproducible in subsequent experiments. During cultural revolution no clinical trials were performed so Dr. Tu bravely volunteered to the first trials. In Hainan first official trials happened on malaria patients. The patients showed much better result than chloroquine (Test samples). Encouraged by this outcome, she moved on to investigate and isolated the pure compound of Artemisia. In 1972 a colorless crystalline substance with a mol wgt. of 282 Da, having molecular formula of C15H22O5 was isolated. The molecule was named as Qinghau su (Artemisinin) from the leaves of Sweet wormwood scientifically known as Artemisia annua, family Compositae. Dr. Y. Tu was awarded with Lasker DeBakey clinical medical research award in 2011 and finally the Nobel Prize in physiology and medicine of artemisinin in 2015. SAR OF ARTEMISININ Tetracyclic structure with a trioxane ring and a lactone ring. Trioxane ring contains a peroxide bridge, the active moiety of the molecule.   MOL. FORMULA: C15H22O5; MOL .MASS: 282.332 Presence of a ‘Trioxane’ moiety which consists of the endoperoxide & doxepin oxygens that is evidently displayed by a simplified version of 3- aryltrioxanes. Modification of 10th position ‘C’ gives a powerful derivative compared to the original compound. Reduction of artemisinin to dihydroartemisinin gives rises to a chiral centre that may ultimately lead to the formation of prodrugs. Artemisinin is a poorly soluble in oils and water so it is administered through oral, IM or rectal route. Semi synthetic like artesunate, artemether arteether and hemisuccinate ester were produced because of poor bioavailability and limit of its effectiveness. To stop the malarial activity, the target was a retroviral aspartyl protease which can be found in the plasmodium faliciparum parasite. The metabolite dihydroartemisinin cleaves the endoperoxide ring inside the erythrocyte.

1. ARTEMISININ
PRESENTED BY:
Ms Himani K S
1st M Pharm
Dept. of Pharmaceutical Chemistry
Jss College of Pharmacy, Mysore
PRESENTED TO:
Dr G V Pujar
Professor & Vice Principal
Dept. of Pharmaceutical Chemistry
Jss College of Pharmacy, Mysore

2. CONTENT
• Introduction
• History
• Chemistry of artemisinin
• Structural activity relationship of artemisinin
• Mechanism of action
• Drug interactions

3. INTRODUCTION AND HISTORY
• Malaria is a very common disease. This probably originated in Africa
around 30 million years ago.
• In 1600s first treatment to malaria was recorded in Peru where native
tribes used bitter bark of cinchona, to reduce the fever and pain.
• In 1897 Sir Ronald Ross described female anopheles mosquito as the
vector of the disease.
• In 1950s the disease rebounded largely due to emergence of parasites
resistant to drugs like chloroquine.
• In 1967 a plant screening research program code named “Project 523”
was set up in China by the People’s liberation army ordered by Mao
Zedong at the request of North Vietnamese.

4. HISTORY
• Under able leadership of Dr. Y. Tu more than 2000 herbs preparations
were investigated . Out of which 640 herbs were hits.
• The turning point came when Sweet wormwood extract showed a
promising degree of inhibition in mouse model.
• Although the progress was not smooth as the observation was not
reproducible in subsequent experiments.
• During cultural revolution no clinical trials were performed so Dr. Tu
bravely volunteered to the first trials.
• In Hainan first official trials happened on malaria patients. The
patients showed much better result than chloroquine (Test samples).

5. HISTORY
• Encouraged by this outcome, she moved on to investigate and
isolated the pure compound of Artemisia.
• In 1972 a colorless crystalline substance with a mol wgt. of 282
Da, having molecular formula of C15H22O5 was isolated. The
molecule was named as Qinghau su (Artemisinin) from the
leaves of Sweet wormwood scientifically known as Artemisia
annua, family Compositae.
• Dr. Y. Tu was awarded with Lasker DeBakey clinical medical
research award in 2011 and finally the Nobel Prize in physiology
and medicine of artemisinin in 2015.

6. CHEMISTRY OF ARTEMISININ
Formula C15H22O5
Molar mass 282.336 g·mol−1
IUPAC name (3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-tri
methyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodio
xepin-10(3H)-one

7. SAR OF ARTEMISININ
• Tetracyclic structure with a trioxane ring and a lactone ring.
• Trioxane ring contains a peroxide bridge, the active moiety of
the molecule.
• MOL. FORMULA: C15H22O5; MOL .MASS: 282.332
• Presence of a ‘Trioxane’ moiety which consists of the
endoperoxide & doxepin oxygens that is evidently displayed by a
simplified version of 3- aryltrioxanes.
• Modification of 10th position ‘C’ gives a powerful derivative
compared to the original compound.

8. SAR OF ARTEMISININ
• Reduction of artemisinin to dihydroartemisinin gives rises to a
chiral centre that may ultimately lead to the formation of
prodrugs.
• Artemisinin is a poorly soluble in oils and water so it is
administered through oral, IM or rectal route.
• Semi synthetic like artesunate, artemether arteether and
hemisuccinate ester were produced because of poor
bioavailability and limit of its effectiveness.

10. MECHANISM OF ACTION
• To stop the malarial activity, the target was a retroviral aspartyl
protease which can be found in the plasmodium faliciparum
parasite.
• The metabolite dihydroartemisinin cleaves the endoperoxide
ring inside the erythrocyte. The drug molecule come in contact
with haem and the ferric oxide breaks the endoperoxide rings.
• This produces free radicals to damage the susceptible protein to
kill the parasite.

11. DRUG INTERACTIONS
• Chloroquine and pyrimethamine may antagonise the activity of
artemisinin whereas mefloquine, quinine,primaquine and
tetracycline potentiate artemisinin.
• The combination of artemisinin derivatives and mefloquine
improves parasite clearance compared with either drug alone.

12. REFERENCE
• Burger’s medicinal chemistry and drug discovery sixth edition, volume 1: Drug
discovery.
• https://en.m.wikipedia.org/wiki/Artemisinin#:~:text=Artemisinin%20(%2F
%CB%8C%C9%91%CB%90t%C9%AA,or%20Medicine%20for%20her
%20discovery.
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671478/