Design, Synthesis and Biological Evaluation of Novel Membrane-Integral Pyrophosphatase Inhibitors.

A larger percentage of the world’s population is at risk of developing a protozoan parasitic infection. Current treatments are failing due to the development of anti-parasitic drug resistance and the associated toxicity of these treatments. Therefore, research into new drug targets and drugs is required. The work presented herein aims to identify new drug leads for the treatment of parasitic infections by targeting a membrane-integral pyrophosphatase (M-PPase) using a structure-based drug design approach. Three approaches were employed to identify novel inhibitors of M-PPase, which lead to the identification of three different classes of inhibitors. The first approach involved the SPROUT design of a indole based putative inhibitor. Due to a number of synthetic difficulties this putative inhibitor could not be synthesised. However, simplification of the indole moiety lead to the identification of the first inhibitor of a M-PPase that was designed using SBDD. The second approach involved the substrate inspired design of a sulfamide fragment, which had a moderate activity when biologically evaluated against TmPPase. This fragment was designed to mimic phosphate in the hydrolytic centre of M-PPase. Expansion of this fragment using SPROUt lead to the identification of a second generation sulfamide fragment, which had an improved potency. Finally, a heterocyclic fragment library was synthesised and biologically evaluated. This library was based upon a heterocyclic fragment identified by collaborators using vHTS. This lead to the identification of a potent thiazole fragment. However, the binding site of this fragment could not be identified so further design could not occur.