Open Source Malaria: Potent Triazolopyrazine-Based Antiplasmodium Agents that Probe an Important Mechanism of Action

Abstract

This thesis describes the design and synthesis of novel triazolopyrazine-based compounds in Open Source Malaria (OSM) Series 4. All aspects of the work are publicly available with experimental results and biological data shared in real time. Chapter 1 provides an overview of malaria and the antimalarial medicines that have been used in the past, those that are currently being used and those being developed for the future. The concept of open science is discussed with respect to open data screens and OSM. Chapter 2 investigates further a series of high value targets (the Frontrunners) with the aim of obtaining a more complete set of biological data. Chapter 3 describes the design, synthesis and in vitro biological evaluation of several novel compounds that probe unexplored areas of SAR. A substitution reaction with a thiol led to an unexpected tele-substitution reaction that is the subject of continuing study. A thorough study of phenyl bioisosteres is conducted in Chapter 4 with key motifs employed including cubane, bicyclo[1.1.1]pentane and carborane. Chapter 5 outlines studies on the series’ mechanism of action. There is a high level of confidence that these compounds act via the inhibition of the parasite’s ability to regulate its intracellular sodium concentration. The biomolecular target, PfATP4, is one that has been implicated for several structurally diverse compounds in development. A predictive modelling competition was run to improve our ability to design future inhibitors. In Chapter 6 is described the synthesis of a number of carboxylic acid containing compounds as a means of reducing unwanted hERG binding. While these compounds resulted in reduced hERG activity, improved solubility and greater metabolic stability, they were found to be less potent in vitro. Successful crowdsourcing of the synthesis of novel Series 4 compounds is described in Chapter 7 through the incorporation of OSM into an undergraduate laboratory class at The University of Sydney.