Date

Friday 23 Jan 2026

Time

15:15 - 15:45

Location

BW019

Supervisor

Hermen Overkleeft

2nd reviewer

Dmitri Filippov

Jury

Alexander Kros

Human neuraminidases (hNEU) are glycoside hydrolases that cut off terminal sialic acids and can affect many biological pathways. Compared with viral neuraminidase (viNEU), hNEU is less explored, but abnormal expression and activity of hNEU isoenzymes (NEU1–4) are related to inflammation, cancer, and neurological functions. Most reported hNEU inhibitors are DANA-based competitive inhibitors and rely on reversible, non-covalent binding. In this project, we aim to develop a different strategy by designing an aziridine-based DANA scaffold as a potential covalent and irreversible neuraminidase inhibitor. The design is based on maintaining key binding features of DANA, while introducing a strained aziridine ring that may undergo nucleophilic ring opening after binding, which may lead to longer-lasting inhibition. This thesis describes the synthetic studies toward the key intermediate for designed target inhibitor. The synthetic route was planned to introduce the main protecting-group pattern early, build a diene precursor, and perform Grubbs ring-closing metathesis (RCM) in the final stage, because metathesis can be sensitive to functional groups and impurities. A practical protecting-group strategy was therefore essential to control chemoselectivity across oxidation, reduction, and functional-group interconversions. Key transformations were discussed from both a mechanistic and experimental perspective, with attention to reproducibility and scalability. A product mass consistent with the Grubbs reaction step was observed, while final purification and full characterization are still in progress. Next steps include purification and characterization the RCM product, completing the synthesis toward the final aziridine-based inhibitor, and evaluating whether the compound shows time-dependent and irreversible inhibition behavior in neuraminidase assays.