The thesis commences with an overview of 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. Whilst the efficacy of these compounds for treatment of malaria are not in doubt, an enormous amount of research has been conducted on the chemical basis for the mode of action of these compounds for killing the malaria parasite. Because of the necessity of the presence of the peroxide as the active pharmacophore, a large amount of ad hoc experimentation has led to the growth of the carbon-centred radical theory for parasiticidal activity, in which a Fenton-type reaction generates O-centred, and then C-centred radicals by abstraction of...[ Read more ]

The thesis commences with an overview of 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. Whilst the efficacy of these compounds for treatment of malaria are not in doubt, an enormous amount of research has been conducted on the chemical basis for the mode of action of these compounds for killing the malaria parasite. Because of the necessity of the presence of the peroxide as the active pharmacophore, a large amount of ad hoc experimentation has led to the growth of the carbon-centred radical theory for parasiticidal activity, in which a Fenton-type reaction generates O-centred, and then C-centred radicals by abstraction of hydrogen atoms from the periphery of the molecule by the O-centred radical. Two agents have been held responsible for generating these species from the artemisinin derivative, namely the free ferrous iron, or ferrous iron complexed in haem.

In this thesis, we examine the effect of these agents, and of thiols both on known and new artemisinin derivatives which were prepared as part of a programme under support from Bayer AG for the development of new antimalarials. The new derivatives, which have been shown in other work to be extremely active against the malaria parasite both in vitro and in vivo, were therefore screened against thiols, and ferrous iron, both in the free state, and in ferrous haem. Thiols were also tested in the presence of ferrous iron. Several reactions involving the oxophilic Lewis acid trimethylsilyl trifluoromethane sulfonate in the presence of thiols were also carried out. In addition, a UV-VIS spectrophotometric examination of the behaviour of the artemisinin derivatives against desferrioxamine and ferrioxamine was also carried out, in order to establish how these reagents inhibit the activity of artemisinin in vitro.

Whilst many of the results obtained are relatively inconclusive, they do indicate that the new artemisinin derivatives react sluggishly with ferrous sulfate in aqueous acetonitrile at room temperature. In addition, whereas the known derivative 10-deoxoartemisinin is relatively easily decomposed under the foregoing conditions, it is unaffected by ferrous haem in aqueous acetonitrile. Thiols in general are also found to react relatively sluggishly with the new artemisinin derivatives. In the case of 10-deoxoartemisinin, an adduct is isolated from its reaction with 2-naphthalenethiol in the presence of ferrous iron. It is concluded that none of the reactions can be involved in any putative biological process which leads to the death of the malaria parasite, as there is no correlation between the reported in vitro activity of the new derivatives, and their ability to react with ferrous iron, with ferrous haem, or with thiols. It is proposed that the peroxide itself must bind into an active site, without disruption. This is in line with the recent discovery that artemisinin acts as an inhibitor of the parasite ca²⁺ transporter PfATP6 in the parasite sarco/endoplasmic reticulum, whereas it has no effect on the mammalian enzyme.

In the second part of the thesis, a new straightforward phase transfer method is disclosed which enables new and known aminoaryl and O-aryl derivatives of dihydroartemisinin to be prepared in an extremely straightforward fashion. The method is applied successfully to a simple preparation of the new artemisinin derivative artelinate, which is a development candidate first prepared at the Walter Reed Army Institute of Research in the USA.