Smyth, E.B., Pisco, J.P., Birchall, K. et al. (4 more authors) (2025) Design and Synthesis of Pyrazoline Inhibitors of SARS-CoV-2 NSP14. ACS Medicinal Chemistry Letters. ISSN: 1948-5875
Abstract
Non-structural protein 14 (NSP14) is a key two-domain protein responsible for maintaining coronavirus replication fidelity, and in its absence reproduction is severely impacted. With the goal of identifying new inhibitors of SARS-CoV-2 NSP14, we selected a previously reported scaffold as an appropriate starting point. Medicinal chemistry exploration provided a series of trisubstituted pyrazolines as inhibitors of NSP14 methyltransferase (MTase) activity, with improved synthetic tractability and in a promising molecular property space. This led to compound 35 as a potent inhibitor of NSP14 MTase with a favorable in vitro ADMET profile, and antiviral activity against SARS-CoV-2 replication. We propose that 35 is a useful chemical probe which is well-positioned to further interrogate in vitro biology and for further optimization toward the treatment of human coronaviruses.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY-NC-ND 4.0). |
Keywords: | Ligands, Inhibition, Inhibitors, Molecules, Peptides and Proteins, SARS-CoV-2 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) |
Date Deposited: | 02 Oct 2025 15:22 |
Last Modified: | 02 Oct 2025 15:22 |
Status: | Published online |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acsmedchemlett.5c00155 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:232436 |
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