Travellers to South America brought various plant products back to Europe. Trees of the genus Cinchona were used as a source of a raw product useful in treating malaria, and a number of other complaints. From the mid-1600s to the mid-1800s powdered quinine bark imported from the wild in South America was the primary treatment for malaria, and it was apparently very effective.

Eventually in 1820 the active ingredient quinine was identified, and then production switched to plantations in Asia. It is said that until the 1930s quinine was the only real treatment for malaria. During the second world war supply difficulties caused research into chemical synthesis of quinine rather than extracting it from Cinchona bark.

This in turn led to the development of other synthetic antimalarial substances

Quinine, chloroquine and mefloquine have a similar molecular structure, composed of a quinoline section - two quite flat aromatic rings including a single nitrogen atom - with small sidegroups and a larger offset section.
These compounds are probably more effective against the stages of the malarial parasite within red blood cells than those inside liver cells.

It is tempting to think that these compounds resemble DNA bases, and that they interfere with DNA replication within the malarial parasite. After all, human red blood cells do not contain a nucleus, and do not need to divide, whereas the malarial parasites need to undergo many cell divisions in order to increase in number.

The main protein inside a red blood cell is haemoglobin, and the malarial parasite breaks this down for its own use in building up its own proteins for growth. This causes the release of the iron-containing haem part of the molecule, which could build up and become toxic, so the parasite detoxifies it by converting it into an insoluble form. It appears that quinine and derivatives interfere with this conversion, so the parasite is killed by buildup of iron compounds.

It was known from ancient Chinese medicine that the sweet wormwood plant Artemisia annua (left) has antimalarial effects, and a the compound artemesinin was identified as the active ingredient.

Artemisinin (below left) has 2 oxygen atoms (red) forming an epoxide bridge across one of the rings in its molecule.

This reacts with the detoxified iron compound and releases free radicals which damage proteins produced by the malarial parasites. It has also been shown to disrupt the normal function of the electron transport chain within mitochondria.

Again this exploits the difference between the human red blood cell - which does not need to produce proteins and also does not contain mitochondria - and the malarial parasite - which needs both.

Unfortunately artemisinin is not very soluble. Several derivative compounds have been produced. Artesunate (middle below) is more water-soluble - because of its side chain - so it may be given by injection.

Other similar synthetically produced compounds are currently being evaluated. For example, OZ 277 (shown below right) also has a similar 3-dimensional structure at one end of the molecule, and the other part of the molecule makes it more soluble and stable in blood plasms. It is being tested for effectiveness against chloroquine-resistant falciparum malaria.