In Chapter 1 of this thesis, decomposition of current clinically-used artemisnins is discussed. Artesunate formulated into rectal capsules undergoes decomposition under the thermal stress testing conditions required to establish the shelf life of the capsules. The amounts of dihydroartemisinin (DHA) formed as one of the degradants is outside the recommended guidelines of the International conference on Harmonization (ICH) guidelines. Our task was to find out the missing degradation products. Therefore, it was necessary to examine the thermal decomposition of artesunate. Dihydroartemisinin would have to be examined as well. Because of the importance of β-artemether as an antimalarial drug, its decomposition would also be examined. Artemisone is the drug developed at HKUST, and for it to...[ Read more ]

In Chapter 1 of this thesis, decomposition of current clinically-used artemisnins is discussed. Artesunate formulated into rectal capsules undergoes decomposition under the thermal stress testing conditions required to establish the shelf life of the capsules. The amounts of dihydroartemisinin (DHA) formed as one of the degradants is outside the recommended guidelines of the International conference on Harmonization (ICH) guidelines. Our task was to find out the missing degradation products. Therefore, it was necessary to examine the thermal decomposition of artesunate. Dihydroartemisinin would have to be examined as well. Because of the importance of β-artemether as an antimalarial drug, its decomposition would also be examined. Artemisone is the drug developed at HKUST, and for it to be successful, it is important to establish its shelf life, and to identify the possible degradants which would be formed. Artesunate was submitted to controlled thermal degradation at 100 ℃ to give various products including remarkable artesunate dimers, β-artesunate, and various products which appear to arise from the degradation of DHA formed in situ. The most interesting product appears to be the formate ester which arises from thermal decomposition of the DHA. The artesunate dimers were prepared independently, and the formate ester was prepared by heating artesunate with formic acid. The thermal decomposition of DHA also gave various products. The most important product appeared to be a rearranged peroxide, a peroxyhemiacetal, which was shown to be an important degradation product appearing inside the capsules. Artesunate and DHA were also submitted to controlled degradation under acidic conditions, and for DHA, under basic conditions as well. The preoxyhemiacetal, and various other products arising via intramolecular aldol reaction were formed. Each of artesunate, DHA and artemisone were submitted to controlled thermal degradation at 40 ℃ in thermostatted bath for a long period of time. An NMR method was used to establish the amount of the degradation taking place. It is shown that artesunate and artemisone have about the same thermal stability, and DHA is less stable.

In Chapter 2, the preparation of new polar artemisinin derivatives is discussed. The artemisinins dihydroartemisinin, artesunate and artemether currently used for treatment of malaria have the problem of neurotoxicity, of which dihydroartemisinin is the most neurotoxic. Artesunate and artemether are readily hydrolyzed or metabolized to dihydroartemisinin. It has been established that the more lipophilic an artemisinin is, the more likely it is to be neurotoxic. Therefore, new derivatives must be polar to attenuate the neurotoxicity and to enhance its systemic properties. The importance of lowering the Log P parameter by incorporating polar elements to enhance systemic properties of artemisinins has been illustrated by the preparation of the new artemisinin artemisone, which is non-neurotoxic, and is much more active than the current artemisinins against the malaria parasite. In this thesis, it is described how we wish to use polar groups to continue on the strategy of developing artemisinins which are non-neurotoxic and very active against the malaria parasite. The plan also would be to make water soluble salts from various derivatives bearing amino groups at C10 of the artemisinin nucleus.

The initial idea was to use the sulfamide group in the 10-sulfamide dihydroartemisinin as a scaffold. Therefore, attempts were made to alkylate and acylate this group, and attach various other polar groups to it. The most active compound made in this way was the benzylpiperazinesulfamide derivative which had an activity in vitro agains the malaria parasite of 10 pg/mL. However, in general, it was not so easy to make such derivatives, because of the poor reactivity of the substituted sulfamide with the dihydroartemisinin. The unsubstituted 10-piperazine DHA derivative was made for the first time, and also other piperazines were also made. However, it was not possible to prepare a stable water soluble salt from one of these derivatives.