Theme 1 Lecture 3

Question 1

Case study 1

Answer 1

Discovery of Artemisinin

Question 2

Discovery of Mefloquine

Answer 2

Cultural revolution in China

Research helped both sides of the war due to the resistant plasmodium strain in the Vietnameses war.

This resulted in the discovery of mefloquine which was curative for chloroquine-resistant malaria.

Question 3

Project 523

Answer 3

This meeting was named after the date it happened in Beijing.
North Vietnam reached out for China’s help due to the resistant plasmodium strain killing more people than the war itself.

Question 4

Youyou Tu

Answer 4

Screened over 2000 extracts, with 640 exhibiting activity.
This included chinese herbal meds and synthetic.
Finally extracts from Artemisia (species of wormwood) found to inhibit P.falciparum by 68%

Question 5

Not reproducible results

Answer 5

This ancient medicine dated back over 2000 years ago but was then later unraveled why

Question 6

Why there was no reproducible results?

Answer 6

Heating the extract was degrading the active ingredient in the aq environment

Question 7

What type of ester is
O-O in a cyclic form

Answer 7

lactone

Question 8

Structure of Artemisinin

Answer 8

7 chiral centres
Unstable endoperoxide
Stable to heat and light
Lactone carbonyl can easily reduced to lactol (dihydro form)
Semi-synthesis was used

Question 9

Further studying of structure

Answer 9

Endoperoxide is key for the activity.
Esterification can be achieved producing the relevant ester sodium artesunate

Question 10

Mode of action

Answer 10

Free heme is crucial which leads to the activation of artemisinin (activator of the endoperoxide)
ROS
Protein alkylation
Doesn’t cause toxicity to humans

Question 11

Artemisinin and heme

Answer 11

Activation: Artemisinin is activated by heme released during hemoglobin digestion by malaria parasites.
Mechanism: Heme breaks artemisinin’s endoperoxide bridge, producing reactive free radicals.
Damage to Parasite: Free radicals damage parasite’s proteins and membranes, causing death.

Question 12

Replacing hydrogen with methyl groups

Answer 12

This helps stabilise the the radical due to the tertiary centre

Question 13

What is the bioactive drug

Answer 13

Dihydroartemisinin
Makes many metabolites som low bioavailability
Loss of the endoperoxide destroys activity

Question 14

What leads to higher water solubility

Answer 14

IV

Question 15

What is ACT?

Answer 15

Combined therapy

Question 16

What other drugs are used alongside the artemisinin in ACT?

Answer 16

Combined with a drug from a different class.
Companion drugs include mefloquine.

Question 17

What clinical benefit does the ACT approach offer against single agent therapies

Answer 17

High efficacy
Fast action
Decreased resistance

Question 18

Case Study 2 Ingenol

Answer 18

Diterpene
Used for treatment of actinic keratosis.

Question 19

Croton Oil

Answer 19

Phorbol esters were tumour promoters in croton oil and is used for cancer research

Question 20

Ingenol esters

Answer 20

They were less active than croton oil phorbol esters
Which was investigated from the other plants of Euphorbia genus.

Question 21

Euphorbia pelpus

Answer 21

8000 plant species treating a range of diseases.

Question 22

E. pelpus sap action

Answer 22

Caused differentiations for a bipolar phenotype and are displayed in melanocytes.

Question 23

What is a diterpene?

Answer 23

Diterpenes are a class of chemical compounds composed of 4 isoprene units

Question 24

Mode of action for Inegnol

Answer 24

Signals through PKC/MEK/ERK pathway= apoptosis
Reduction of long term cell viability through interleukin pathways
Common side effect si skin irritation