Synthesis of a Range of Guanidinium-based Compounds and their Inhibition of Trypsin

Abstract

The objective of the research that has been carried out during this PhD work is to synthesise, characterise and evaluate a series of guanidine-based pyridines, and related compounds, as bovine trypsin inhibitors.Chapter 1 introduces the chemistry of Weinreb amides and guanidines, and discusses their properties, methods for their synthesis and their applications. Both these groups feature in the approaches to achieving the aims of this study. Chapter 2 describes the chemical synthesis of guanidine-based pyridines and some aryl and heteroaryl analogues, using the well-established mercury-based S- methyl isothiourea guanidinylation reaction. In order to probe the relevance of the guanidine unit, a modified method from the literature was used to prepare amidines which were also fully characterized and discussed in the second chapter.The twenty-one final compounds were tested as competitive inhibitors against pancreatic trypsin using a kinetic study. The Ki values for the prepared inhibitors were determined by assessing the effect different concentrations of each inhibitor have upon the trypsin catalysed hydrolysis of α-N-benzoyl-L-arginine-ρ-nitroanilide hydrochloride (L-BAPA) at pH 7.10 when [So]<< Km. The results of this study are described in Chapter 3. Different Ki values were recorded for the prepared compounds, showing that inhibitor type and the position of the second substituent in the pyridine ring leads to different potency against trypsin (Ki= 0.00825 - 26.078 mM).