Design and organic synthesis of non-carbohydrate glycomimetics towards galectin-3 inhibitors as drug leads

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with
neuroinflammation and microglial dysregulation. Galectin-3 (gal-3), a β-galactoside-binding
protein expressed in microglia, has been identified as an upstream regulator of neuroinflammatory
responses and is increasingly recognized as a potential therapeutic target in AD. This Master’s
thesis focuses on the design and organic synthesis of non-carbohydrate glycomimetics targeting
gal-3, with the aim of generating drug-like inhibitors suitable for AD treatment.
Inspired by the clinically advanced gal-3 inhibitor GB1211, a novel scaffold was designed in
which a triazole moiety was replaced by a pyrazole to reduce polar surface area and improve
predicted ADME properties, including intestinal permeability and oral absorption. Several
synthetic routes were explored to access the target compound. While key transformations proved
reproducible, challenges associated with oxidation and alkynylation steps limited material
availability.
Computational ADME analysis suggested that the pyrazole-containing scaffold may possess
improved drug-like properties compared to its triazole analogue. A fluorescence polarization assay
performed on limited material indicated weak gal-3 inhibition, likely influenced by low yield and
mass compromising weighing accuracy, as well as sample impurities. Despite these limitations,
this work demonstrates the feasibility of scaffold modification to target physicochemical properties
and provides valuable synthetic insights for the future development of gal-3 inhibitors as potential
therapeutic leads for Alzheimer’s disease.

Popular Abstract

Alzheimer’s disease is a brain disorder that gradually degrades memory, cognitive function, and the ability to perform everyday tasks. Common research explains how protein depositions, called amyloid plaques and tau tangles, are found in the brains of affected patients. However, increasing evidence shows that chronic inflammation in the brain plays an important role in disease progression. One protein involved in this inflammatory response is galectin-3, which is highly expressed in the brain’s immune cells and has been linked to increased inflammation and the cognitive decline in Alzheimer’s disease.

This Master’s thesis explores the development of new small molecules designed to block galectin-3. Instead of using sugar-based molecules this project focuses on non-carbohydrate glycomimetics, sugar-mimicking molecules, that aim to retain strong binding while being more suitable as medicines. Using an existing galectin-3 inhibitor as inspiration, a new molecular scaffold was designed with improved predicted properties for absorption and transport in the body, including the ability to reach the brain.

Several strategies were planned and executed to synthesize the target compound. Although the complete synthesis could not be fulfilled within the project timeframe, many key reaction steps were successfully developed and evaluated. Preliminary biological testing suggested weak inhibition of galectin-3, but the results were limited by the small amount of material obtained.

Overall, this work contributes new design ideas and synthetic knowledge toward the development of galectin-3 inhibitors and highlights both the potential and the challenges of targeting neuroinflammation in Alzheimer’s disease.

• author: Persson, Philip
• supervisor: Ulf Nilsson
• organization: Centre for Analysis and Synthesis
• course: KASM05 20252
• year: 2026
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: organic chemistry, alzheimer's disease, inflammation
• language: English
• id: 9221889
• date added to LUP: 2026-02-10 14:28:33
• date last changed: 2026-02-10 14:28:33