Synthesis of Polyamine Analogues As Antimalarial and Antifungal Agents

Ross, William Ferguson (1999) Synthesis of Polyamine Analogues As Antimalarial and Antifungal Agents. PhD thesis, University of Glasgow.

Abstract

This research project was concerned with two areas, the synthesis of new antimaiarial agents and the synthesis of new antifungai agents. Malaria is spread to humans by parasites of the Plasmodium genus. The vector is the female Anopheles mosquito. It is the most important parasitic disease affecting mankind and kills about two million people every year. The parasites have developed resistance to the majority of the available treatments, including the naturally occurring compound quinine (A) and the synthetic drug chloroquine (B). Hence there is an urgent need for new antimalarial agents. The resistance of fungi which grow on important food crops to available fungicides has increased the need to find new antifungai agents. Polyamines such as putrescine (C) and spermine (D) are widespread in nature. They are important in cell development and are vital for normal cell growth. The study of these compounds, particularly their synthesis and biosynthetic enzymes, has stimulated the development of polyamines to treat a number of diseases including malaria and plant fungal diseases. Previous workers within our group had synthesised a number of acyclic putrescine analogues such as (E) which was found to have promising antimalarial and antifungal activity. We wanted to investigate the properties of a number of bicyclic putrescine analogues. In this work we have developed a route to prepare novel symmetrical and unsymmetrical putrescine analogues of the general structure (F). We have also synthesised a number of polyamine analogues (G), (H) and (I), varying the distance between the nitrogen atoms. Antimalarial testing was carried out by Prof. Steven Phillips and Ms. Fiona McMonagle in the Division of Infection and Immunity, University of Glasgow. Antifungal tests were performed by Dr Dale Walters at the Scottish Agricultural College, Auchincruive. Measurements of the in vitro antimalarial activity of (G) showed an improvement as the distance between the nitrogen atoms increased. The most active had activity comparable to chloroquine (B). Unfortunately they showed no in vivo activity. Analogues (H) showed good in vitro activity which improved as the distance between the nitrogen atoms decreased. The most active compounds (I) showed similar activity to the corresponding analogues (G). The in vitro antifungal results followed a similar pattern. The most active compounds substantially inhibit fungal growth, although not all the compounds have yet been evaluated. A number of compounds containing pyridyl rings were prepared with general structures (J), (K) and (L). In each case those compounds bearing benzyl or cyclohexylmethyl substituents displayed the greatest antimalarial activity. In vitro antimalarial activity increased from (J) to (K) but the results we have so far for (L) are disappointing. The most active analogue (K) in vitro was tested for in vivo activity, but was found to be inactive. The in vitro antifungfal testing results for (J) were disappointing. None of the compounds showed appreciable activity at 0.1 mM. We are awaiting the results for compounds (K) and (L).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: David Robins
• Keywords: Organic chemistry, Pharmacology
• Date of Award: 1999
• Depositing User: Enlighten Team
• Unique ID: glathesis:1999-76123
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 16:37
• Last Modified: 19 Nov 2019 16:37
• URI: https://theses.gla.ac.uk/id/eprint/76123