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Design and Synthesis of Pyrazoline Inhibitors of SARS-CoV‑2 NSP14
Elliott B Smyth1,2, João P Pisco1, Kristian Birchall1
1LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, U.K.
ACS Medicinal Chemistry Letters
|October 15, 2025
Summary
Researchers identified a new compound, 35, that potently inhibits SARS-CoV-2 non-structural protein 14 (NSP14) methyltransferase activity. This compound shows promise for developing novel antiviral treatments against human coronaviruses.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- Non-structural protein 14 (NSP14) is essential for coronavirus replication fidelity.
- Inhibition of NSP14 is a potential strategy for developing antiviral therapies.
Purpose of the Study:
- To identify novel inhibitors of SARS-CoV-2 NSP14 methyltransferase (MTase) activity.
- To develop a chemical probe for further research and optimization.
Main Methods:
- Medicinal chemistry exploration of a known scaffold.
- Synthesis and evaluation of trisubstituted pyrazolines.
- In vitro assessment of NSP14 MTase inhibition and ADMET properties.
- Antiviral activity testing against SARS-CoV-2.
Main Results:
- A series of trisubstituted pyrazolines were identified as NSP14 MTase inhibitors.
- Compound 35 demonstrated potent NSP14 MTase inhibition.
- Compound 35 exhibited a favorable in vitro ADMET profile and antiviral activity against SARS-CoV-2.
Conclusions:
- Compound 35 is a potent inhibitor of SARS-CoV-2 NSP14 MTase.
- Compound 35 serves as a valuable chemical probe for further investigation.
- Compound 35 holds potential for optimization as a therapeutic agent against human coronaviruses.
