The history and development of the Chinese peroxidic sesquiterpene qinghaosu or artemisinin, and its conversion into the current derivatives artemether and artesunate which are used in the chemotherapy of malaria, are briefly reviewed. Because of peroxide is shown to be necessary for antimalarial activity, a large amount of work published by various groups has led to the growth of the carbon-centred radical theory for parasiticidal activity. It is assumed that a Fenton-type reaction takes place. The peroxide is reduced by ferrous iron, either free, or in haem, to give O-centred radicals. The O-centred radicals then are transformed into C-centred radicals by abstraction of hydrogen atoms from the periphery of the molecule. The types of products formed - 4-hydroxy-2-deoxyartemisinin and f...[ Read more ]

The history and development of the Chinese peroxidic sesquiterpene qinghaosu or artemisinin, and its conversion into the current derivatives artemether and artesunate which are used in the chemotherapy of malaria, are briefly reviewed. Because of peroxide is shown to be necessary for antimalarial activity, a large amount of work published by various groups has led to the growth of the carbon-centred radical theory for parasiticidal activity. It is assumed that a Fenton-type reaction takes place. The peroxide is reduced by ferrous iron, either free, or in haem, to give O-centred radicals. The O-centred radicals then are transformed into C-centred radicals by abstraction of hydrogen atoms from the periphery of the molecule. The types of products formed - 4-hydroxy-2-deoxyartemisinin and furan acetate derivatives - are supposed to indicate the intermediacy of the C-centred radicals.

Our group has prepared a large number of new artemisinin derivatives substituted at C10 by amino groups derived from primary and secondary amines. Some of these new derivatives are very active against the malaria parasite both in the in vitro screen conducted against malaria parasites cultured in red blood cells, and in vivo against malaria parasite (Plasmodium berghei) in infected mice. Because they are much more active than the current artemisinins, it is worthwhile to test their chemical reactivity against ferrous iron. It has been previously claimed in the literature, that more reactive artemisinin derivatives react more readily with ferrous iron

Artemisinin, artesunate, 10-deoxoartemisinin, and the new amino derivatives were tested by reacting with ferrous sulfate under aqueous conditions in the absence and presence of ascorbic acid. The products were isolated, and identified by comparison with literature data. The rates of the reactions were also measured by examining the rate of disappearance of the starting compound as compared to artemisinin and artesunate. Firstly, the rates of the reactions were widely different for different derivatives. While the known artemisinin derivatives gave 4-hydroxy-2-deoxyartemisinin and furan acetate products, the C10 amino compounds also tended to give products arising via deoxygenation of the peroxide. The ascorbic acid tends to accelerate the reactions under aqueous conditions, but it does not change the product distribution at all. Because it is known to antagonize the effect of artemisinins against the malaria parasite, it is believed that this effect is due to the ascorbic acid encouraging the competitive decomposition of the artemisinin derivative.

When ferrous bromide was used under anhydrous conditions, the amino derivatives obtained from the primary amines gave a new type of product, a cyclic enamine arising from reduction of the peroxide bridge. The best way to explain the formation of these compounds is via ring opening to free hydroperoxide and reclosure to give the cyclic enamine. However, attempts to induce ring opening in the absence of ferrous iron were not successful. Because under these conditions, the formation of products previously believed to indicate the presence of free radicals was minimal, we do believe the C-centred radical hypothesis can be discounted by the result of our experiments.