Chagas Disease : Synthetic Studies Towards Target Identification and Potential Treatment

Abstract

Introduction: Chagas disease, caused by Trypanosoma cruzi, remains a significant public
health challenge, particularly among socioeconomically disadvantaged populations in
developing countries. Although two drugs are currently available, their use is associated to
severe side effects, and they are only widely accepted as a treatment against the acute phase of
the disease.
Background: A Waltherione F derivative with promising potency (IC50: 6 nm), was recently
synthesized at RG discovery. Identifying the target of the Waltherione F like compounds is of
great interest as it would allow for in silico techniques, significantly accelerating the drug
discovery process. The recently published photoproximity labelling method was chosen as the
preferred approach, although it requires the synthesis of multiple chemical components.
Aim(s): The primary aim of this thesis is to synthesize a component for the photoproximity
labelling, namely a ligand that has affinity for the Waltherione F target and can be attached to
a Boc-PEG3 moiety. Several analogues of the promising Waltherione F derivative will also be
synthesized with the aim of further investigate the structure-activity relationship and improving
solubility.
Methods: The Conrad Limpach synthesis will be employed for constructing quinoline
scaffolds. Position 3 of the quinoline ring will be functionalized by substituting ethyl
acetoacetate at position 2, prior to cyclization.
Results: The ligand for photo proximity labelling has been successfully synthesized however,
the Boc-PEG3 moiety could not be attached due to time constraints. Four analogues of
promising Waltherione F derivatives have been synthesized. Potency cannot yet be reported, as
results from biological testing remain pending.
Conclusion: Introducing substituents at position 2 of ethyl acetoacetate, prior to cyclization,
has proven to be a versatile and reliable method for accessing previously synthetically
unachievable compounds. Additional work is required for attaching the Boc-PEG3 moiety to
the photoaffinity ligand

Popular Abstract

Chagas disease is a serious tropical illness caused by a microscopic parasite called
Trypanosoma cruzi. It is often referred to as a neglected disease because it mainly affects the
poorest populations in underdeveloped countries and has received little attention over the years.
The disease has two stages, an early acute phase and a lifelong chronic phase. The acute stage,
lasting 2 to 4 weeks, often goes unnoticed or causes only mild symptoms, like those of a
common cold. The infected person then decades later moves to the chronic phase which
commonly leads to serious health issues such as heart disease, digestive complications and
nervous system disorders. Currently, there are only two drugs available, and both can cause
toxic side effects. More importantly, they are only effective if given during the early stage of
infection.
To find better treatments, the Drugs for Neglected Diseases initiative, a non profit organization
based in Switzerland, launched a project to develop safer and more effective drugs. Their work
focused on modifying Waltherione F, a naturally occurring compound with known antiparasitic
properties. A drug discovery company, RG Discovery, later joined the effort and succeeded in
creating a promising new molecule derived from this natural compound.
In the next phase of the project, where this thesis contributes, scientists set out to understand
how these compounds actually work. To do this, they used a new method called photoproximity
labeling, which can help pinpoint the drugs exact target inside the parasite. This technique
requires attaching a flexible chemical handle known as Boc-PEG3 to a specially designed
molecule that has affinity for the target.
The specially designed molecule has been successfully synthesized, where only attaching the
Boc-PEG3 handle remains for future contributors. Several more soluble versions of the
promising compound were designed and synthesized, including some that had been too difficult
to make using earlier methods. These new versions are now being tested for their ability to kill
the parasite, with the hope of getting a step closer to a new generation of safer and more
effective treatments for Chagas disease.

• author: Miladinovic, Kristian
• supervisor: Johan Wennerberg; Thomas Brimert
• organization: Department of Chemistry
• course: KEML10 20251
• year: 2025
• type: M2 - Bachelor Degree
• subject: Chemistry
• keywords: Chagas Disease, Conrad Limpach reaction, Trypanosoma cruzi, Quinoline, Waltherione F, Organic Chemistry
• language: English
• id: 9198503
• date added to LUP: 2025-06-13 12:01:16
• date last changed: 2025-06-13 12:01:16