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

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

tele-substitution reactions in the synthesis of a promising class of 1,2,4-Triazolo[4,3- a]pyrazine-based antimalarials

We have discovered and studied a tele-substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base or the use of softer nucleophiles, less polar solvents, and larger halogens on the electrophile. Using results from X-ray crystallographic and isotope labeling experiments, a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active antiplasmodium compounds of Series 4 of the Open Source Malaria consortium. © 2020 American Chemical Society. All rights reserved

Dataset for Tele-substitution Reactions in the Synthesis of a Promising Class of Antimalarials

This dataset is supporting information for article "Tele-substitution Reactions in the Synthesis of a Promising Class of Antimalarials". It includes raw NMR data and archive of laboratory journal. The study originates from the work on Open Source Malaria (OSM) Series 4. During SAR exploration of OSM Series 4 we have noticed unusual tele-substitution reaction in 1,2,4] triazolo [4,3-a] pyrazine system. This transformation was studied to understand the influence of different factors (structure of triazolopyrazine, nucleophile and reaction conditions) on the reaction outcome. As a result of series of experiments, including deuteration labelling the mechanism of the tele-substitution reaction was proposed. First zip file, Tele-substitution laboratory jornal.zip, is an archive of the laboratory journal in a raw format with all related information. This information could be used by other researchers to track back the experiments and obtained further inside with more details compared to the journal style information. Thus, some information that could be useful for researchers never gets published, especially unsuccessful experiments. Second zip file, Tele-substitution NMR_DATA.zip, is a collection of unprocessed NMR spectra files alongside with processed files in different formats. Provided files give the flexibility of easier comparison of spectra and the ability to zoom in and inspect some areas of spectra closer if required. This study is part of the Open Source Malaria Project

The past, present and future of anti-malarial medicines

Abstract Great progress has been made in recent years to reduce the high level of suffering caused by malaria worldwide. Notably, the use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy (ACT) for malaria treatment have made a significant impact. Nevertheless, the development of resistance to the past and present anti-malarial drugs highlights the need for continued research to stay one step ahead. New drugs are needed, particularly those with new mechanisms of action. Here the range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine. A number of new potential anti-malarial drugs currently in development are outlined, along with a description of the hit to lead campaign from which it originated. Finally, promising novel mechanisms of action for these and future anti-malarial medicines are outlined

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

We have discovered and studied a telesubstitution reaction in a biologically important heterocyclic ring system. Conditions that favour the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium. Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link https://ses.library.usyd.edu.au/handle/2123/21890 . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds. </p

tele-Substitution Reactions in the Synthesis of a Promising Class of 1,2,4-Triazolo[4,3a]pyrazine-Based Antimalarials

We have discovered and studied a tele-substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base or the use of softer nucleophiles, less polar solvents, and larger halogens on the electrophile. Using results from X-ray crystallographic and isotope labeling experiments, a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active antiplasmodium compounds of Series 4 of the Open Source Malaria consortium