Synthesis and evaluation of tetraazamacrocycles as antiparasitic agents

Reid, Caroline Mary (2006) Synthesis and evaluation of tetraazamacrocycles as antiparasitic agents. PhD thesis, University of Glasgow.

Abstract

Human African Trypanosomiasis (HAT), commonly known as Sleeping Sickness, is endemic in over 36 countries in sub-Saharan Africa. It is caused by the parasitic subspecies Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, which is transmitted to humans by the tsetse fly. The World Health Organisation estimates that 0.5 million people are currently infected with the disease, with a further 60 million at risk. HAT is lethal if left untreated and there is no vaccine available. There are only four accessible drugs, which are all inadequate and highly toxic. Thus there is a vital need for novel anti-parasitic agents.

Compounds interfering with polyamine biosynthesis or function have shown potential use as anti-cancer, anti-HIV, anti-fungal and antiparasitic agents. The overall aim of this work was to synthesise novel macrocyclic polyamines containing different substituents to increase the toxicity against T. brucei.

Twenty racemic substituted tetraazamacrocycles B have been synthesised using an iron template method in good yields (54-100%) from triethylenetetraamine and aromatic glyoxal derivatives A. The R-groups were aromatic or heteroaromatic and were selected to give compounds with varying electronic demand and a broad range of log P values. Two derivatives contain parasite-specific recognition motifs were also prepared. The compounds were tested against T. brucei and several of the analogues displayed high activity. Some of these azamacrocycles were also tested for activity against the malarial parasite Plasmodium falciparum, and for oligopeptidase B (OPB) inhibition, with a number of compounds exhibiting promising results.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Engineering > Infrastructure and Environment
• Supervisor's Name: Robins, Prof. D.J.
• Date of Award: 2006
• Depositing User: Mrs Marie Cairney
• Unique ID: glathesis:2006-6257
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Apr 2015 10:48
• Last Modified: 02 May 2018 14:41
• URI: https://theses.gla.ac.uk/id/eprint/6257