TY - GEN
AU - Smyth, Elliott B.
AU - Pisco, João P.
AU - Birchall, Kristian
AU - Upfold, Nicole S.
AU - Patel, Arvind H.
AU - Foster, Richard
AU - Large, Jonathan M.
PY - 2025
DA - September
TI - Design and synthesis of pyrazoline inhibitors of SARS-CoV-2 NSP14
DO - https://doi.org/10.1021/acsmedchemlett.5c00155
AB - 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.
PB - ACS Publications
UR - https://eprints.gla.ac.uk/363877/
KW - Coronavirus (COVID-19)
ER