Design and synthesis of pyrazoline inhibitors of SARS-CoV-2 NSP14

Authors: Smyth, Elliott B. ;

Pisco, João P.;

Birchall, Kristian;

Upfold, Nicole S.;

Patel, Arvind H. ;

Foster, Richard;

Large, Jonathan M.

Source: ACS Medicinal Chemistry Letters

Full text

: https://doi.org/10.1021/acsmedchemlett.5c00155

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.

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https://creativecommons.org/licenses/by-nc-nd/4.0/

Cite as

Smyth, E., Pisco, J., Birchall, K., Upfold, N., Patel, A., Foster, R. & Large, J. 2025, 'Design and synthesis of pyrazoline inhibitors of SARS-CoV-2 NSP14', ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.5c00155

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DOI: https://doi.org/10.1021/acsmedchemlett.5c00155

Repository URI: https://eprints.gla.ac.uk/363877/