Synthetic and biological studies of antiparasitic natural product derivatives

Trypanosomiasis and Leishmaniasis are tropical diseases caused by the parasites Trypanosoma and Leishmania, that cause severe medical and economical problems for millions of people in the developing world. Trypanosomiasis can be divided into African and American trypanosomiasis, which are caused by Trypanosoma brucei and Trypanosoma cruzi respectively. There are more than 20 different species of Leishmania worldwide that cause Leishmaniasis, but the most severe infection, visceral leishmaniasis, is caused by Leishmania donovani. Both diseases are transmitted by blood sucking insects like the tsetse fly and the sand fly. The majority of existing drugs for trypanosomiasis and leishmaniasis are either too toxic or have low efficacy, and in some cases parasites have also developed resistance. There is therefore a pressing need to develop new chemotherapeutic agents, and in this context, the enzyme trypanothione reductase (TryR) has emerged as an attractive validated target for drug design. The natural product cadabicine, extracted from the plant Cadaba farinosa, is a diphenyl ether-containing macrocyclic spermidine alkaloid which has been identified as a potential inhibitor of TryR by virtual screening. In order to investigate the potential of cadabicine as a TryR inhibitor, an efficient synthetic route to the natural product was delivered. This work was focused on the preparation and combination of three key synthetic units, namely an orthogonally protected spermidine derivative and two functionalised cinnamic acid units. This approach lead to the formation of the macrocycle by an intramolecular nucleophilic aromatic substitution followed by a convenient conversion to the natural product. In the same manner cyclic and noncyclic analogues of cadabicine were prepared, in order to examine the structure-activity relationship of these alkaloids to TryR.EThOS - Electronic Theses Online ServiceGBUnited Kingdo