Open Source Malaria: Medicinal Chemistry of Triazolopyrazines towards New Antimalarial Drug Candidates

Abstract

This thesis focuses on the synthesis of novel triazolopyrazines within OSM Series 4. The design and synthesis of new triazolopyrazine targets are described, and the results of the in vitro biological evaluation of the prepared compounds are presented. Detailed mechanistic studies of nucleophilic aromatic substitution reactions in the triazolopyrazine system are also described. Chapter 1 surveys currently available methods for the halogenation of N-heterocycles and introduces the most common reactions for functionalising halogenated N-heterocycles. Chapter 2 describes the design, synthesis and biological evaluation of 3-substituted triazolopyrazines bearing cyclic amines as pendant groups in the ’north east’ of the molecule. These compounds were prepared in an attempt to improve the solubility of OSM Series 4 lead compounds. In the effort to synthesise these targets direct nucleophilic aromatic substitution along with Buchwald-Hartwig amination was explored. Chapter 3 outlines further exploration of 3-substituted triazolopyrazines, by incorporating a variety of polar aromatic substituents using the Suzuki coupling. As a result of this effort, several highly promising compounds with IC50 < 0.150 μM were identified . Chapter 4 describes mechanistic studies of an unusual tele-substitution reaction observed and characterised when attempting SNAr reactions with this triazolopyrazine system. It was found that the tele-substitution pathway of the reaction is made more likely by the use of stronger nucleophiles, triazolopyrazines with bulkier halogens, and less polar solvents.