The aim of the first project described in this Thesis is to prepare and evaluate the antimalarial activities of structural analogues of the naturally-occurring peroxidic antimalarial compound artemisinin. Because of the expense of extracting artemisinin, and converting it into its derivatives, it is necessary to construct simple structural analogues which contain the active peroxide pharmacophore of the artemisinin. Therefore, the preparation of a relatively little known class of compound called 1,2,4-dioxazolidines has been examined. These compounds have a five-membered ring containing a peroxide and a nitrogen atom. Several such compounds are prepared from cyclopentanone, cyclohexanone, 4-methyl and 4-tert-butylcyclohexanone, and from 2-adamantanone by treatment of the ketones with am...[ Read more ]

The aim of the first project described in this Thesis is to prepare and evaluate the antimalarial activities of structural analogues of the naturally-occurring peroxidic antimalarial compound artemisinin. Because of the expense of extracting artemisinin, and converting it into its derivatives, it is necessary to construct simple structural analogues which contain the active peroxide pharmacophore of the artemisinin. Therefore, the preparation of a relatively little known class of compound called 1,2,4-dioxazolidines has been examined. These compounds have a five-membered ring containing a peroxide and a nitrogen atom. Several such compounds are prepared from cyclopentanone, cyclohexanone, 4-methyl and 4-tert-butylcyclohexanone, and from 2-adamantanone by treatment of the ketones with ammonia and hydrogen peroxide. The best set of conditions involve the use of aqueous concentrated ammonia, 30% hydrogen peroxide, and methanol in the presence of the sodium salt of EDTA according to conditions developed by Hawkins in the 1960s. The compounds have been characterized by spectroscopy and by X-ray crystallography, and by conversion into substituted urea derivatives by treatment with aryl isocyanates. The urea derivatives have remarkable thermal stabilities, and the phenyl derivative of the dioxazolidine derived from cyclohxanone is shown to decompose above 200 °C. These compounds are therefore substantially more stable than artemisinin derivatives currently used for treating malaria. Both the parent compounds and the urea derivatives possess very good activities in vitro against chloroquine resistant and sensitive strains of Plasmodium falciparum, and show a lower limit of IC₅₀ values at 18 ng mL^-1. The results are noteworthy, as the corresponding symmetrically substituted trioxolanes possess no measurable activities.

In the second part of the thesis, a new project has commenced that has the aim of evaluating the biological activities of small heterocyclic bicylo[3,3,0]octanes for antimalarial activities, as quorum-sensing agents for bacterial growth, and as agonists of the ATP-ase type calcium pump situated on the endoplasmic reticulum and which regulates intracellular calcium stores. The selected compounds are expected to behave in analogous fashion to the naturally occurring plakortones. The initial stages of the work involve assessing various preparative routes to a series of bicyclic isoxazolidines, which are based on 1,3-dipolar cycloaddition reactions of nitrones with prop-1-ene-1,3-sultone. A series of nitrones were prepared, and treated with the sultone to given the cycloadduct sultones in quite good yields. The sultones are unstable, but were able to be converted into stable bicyclic sultams by treatment with primary amines. One of the bicyclic lactams has promising activity in vitro against chloroquine resistant and sensitive strains of malarial parasite P. falciparum. Therefore this compound class represents a new type of chemical entity which has antimalarial activities, and therefore has the potential to be developed into a new drug for malaria. The biological activities as quorum sensing agents and as SERCA agonists need to be evaluated.