Theme 1 Lecture 3 Flashcards
Case study 1
Discovery of Artemisinin
Discovery of Mefloquine
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.
Project 523
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.
Youyou Tu
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%
Not reproducible results
This ancient medicine dated back over 2000 years ago but was then later unraveled why
Why there was no reproducible results?
Heating the extract was degrading the active ingredient in the aq environment
What type of ester is
O-O in a cyclic form
lactone
Structure of Artemisinin
7 chiral centres
Unstable endoperoxide
Stable to heat and light
Lactone carbonyl can easily reduced to lactol (dihydro form)
Semi-synthesis was used
Further studying of structure
Endoperoxide is key for the activity.
Esterification can be achieved producing the relevant ester sodium artesunate
Mode of action
Free heme is crucial which leads to the activation of artemisinin (activator of the endoperoxide)
ROS
Protein alkylation
Doesn’t cause toxicity to humans
Artemisinin and heme
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.
Replacing hydrogen with methyl groups
This helps stabilise the the radical due to the tertiary centre
What is the bioactive drug
Dihydroartemisinin
Makes many metabolites som low bioavailability
Loss of the endoperoxide destroys activity
What leads to higher water solubility
IV
What is ACT?
Combined therapy
What other drugs are used alongside the artemisinin in ACT?
Combined with a drug from a different class.
Companion drugs include mefloquine.
What clinical benefit does the ACT approach offer against single agent therapies
High efficacy
Fast action
Decreased resistance
Case Study 2 Ingenol
Diterpene
Used for treatment of actinic keratosis.
Croton Oil
Phorbol esters were tumour promoters in croton oil and is used for cancer research
Ingenol esters
They were less active than croton oil phorbol esters
Which was investigated from the other plants of Euphorbia genus.
Euphorbia pelpus
8000 plant species treating a range of diseases.
E. pelpus sap action
Caused differentiations for a bipolar phenotype and are displayed in melanocytes.
What is a diterpene?
Diterpenes are a class of chemical compounds composed of 4 isoprene units
Mode of action for Inegnol
Signals through PKC/MEK/ERK pathway= apoptosis
Reduction of long term cell viability through interleukin pathways
Common side effect si skin irritation
