Research output: Contribution to journal › Article › peer-review
Expanding the antiviral arsenal: N-arylated 1,2,4-oxadiazol-5(4H)-ones show high activity against orthopoxviruses. / Semenov, Artem V.; Baykov, Sergey V.; Soldatova, Natalia S. et al.
In: European Journal of Medicinal Chemistry, Vol. 300, 118124, 15.12.2025, p. 118124.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Expanding the antiviral arsenal: N-arylated 1,2,4-oxadiazol-5(4H)-ones show high activity against orthopoxviruses
AU - Semenov, Artem V.
AU - Baykov, Sergey V.
AU - Soldatova, Natalia S.
AU - Geyl, Kirill K.
AU - Shetnev, Anton A.
AU - Boyarskiy, Vadim P.
AU - Yusubov, Mekhman S.
AU - Bormotov, Nikolai I.
AU - Serova, Olga A.
AU - Shishkina, Larisa N.
AU - Ovchinnikova, Alena S.
AU - Odnoshevsky, Dmitrii A.
AU - Pyankov, Oleg V.
AU - Borisevich, Sophia S.
AU - Gorohov, Yakov V.
AU - Nikitin, Vladimir N.
AU - Shcherbakov, Dmitry N.
AU - Yarovaya, Olga I.
AU - Salakhutdinov, Nariman F.
AU - Postnikov, Pavel S.
N1 - Virological studies were carried out with financial support from the State assignment of the State Research Centre of Virology and Biotechnology VECTOR. Synthetic study was supported by the Russian Science Foundation, project 21-73-20031-P. This work was partially supported by the Ministry of Science and Higher Education of the Russian Federation within the governmental order for N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS (project FWUE-2025-0006). The bioinformatic analysis was performed within the framework of the state assignment of the Ufa Institute of Chemistry UFRC RAS Kinetic, Spectral-Luminescent, and Theoretical Investigation of Key Intermediates in Chemical and Biochemical Oxidation Processes 125020601626–9. The authors are grateful to the theoretical group “Quanta and Dynamics” for theoretical study https://monrel.ru/about_en/
PY - 2025/9/8
Y1 - 2025/9/8
N2 - The study presents the discovery of a novel class of N-arylated 1,2,4-oxadiazol-5(4H)-ones as potent inhibitors of orthopoxviruses, including the variola virus (VARV). Through systematic structural modifications, two lead compounds, 4 (4-CF3/4-NO2) and 10 (4-I/4-NO2), demonstrated in submicromolar concentration antiviral activity against Vaccinia virus (VACV), cowpox virus (CPXV), ectromelia virus (ECTV), and VARV, with selectivity indices (SI) up to 13738. Studies of mechanisms of action, including time-of-addition experiments and molecular modeling, have shown that these compounds can target the conserved protein p37, which plays a key role in the envelope of the virus. Furthermore, bioinformatic analysis revealed potential interactions with late-stage replication proteins encoded by the A39R and C8L genes. The synthesized derivatives showed activity higher than that of Cidofovir, although they were less effective than that of Tecovirimate. This work highlights the potential of oxadiazolone-based scaffolds as broad-spectrum antipoxviral agents that meet the unmet need for therapy against emerging and re-emerging orthopoxviral threats.
AB - The study presents the discovery of a novel class of N-arylated 1,2,4-oxadiazol-5(4H)-ones as potent inhibitors of orthopoxviruses, including the variola virus (VARV). Through systematic structural modifications, two lead compounds, 4 (4-CF3/4-NO2) and 10 (4-I/4-NO2), demonstrated in submicromolar concentration antiviral activity against Vaccinia virus (VACV), cowpox virus (CPXV), ectromelia virus (ECTV), and VARV, with selectivity indices (SI) up to 13738. Studies of mechanisms of action, including time-of-addition experiments and molecular modeling, have shown that these compounds can target the conserved protein p37, which plays a key role in the envelope of the virus. Furthermore, bioinformatic analysis revealed potential interactions with late-stage replication proteins encoded by the A39R and C8L genes. The synthesized derivatives showed activity higher than that of Cidofovir, although they were less effective than that of Tecovirimate. This work highlights the potential of oxadiazolone-based scaffolds as broad-spectrum antipoxviral agents that meet the unmet need for therapy against emerging and re-emerging orthopoxviral threats.
KW - Antiviral activity
KW - Bioinformatics
KW - Cowpox virus
KW - Molecular modeling
KW - Mousepox virus
KW - N-Aryl-oxadiazol-5(4H)-Ones
KW - Orthopoxviruses
KW - Vaccinia virus
KW - Variola virus
KW - p37
UR - https://www.scopus.com/pages/publications/105015653493
UR - https://www.mendeley.com/catalogue/d6bed69a-74b4-3dd3-a68a-39c4af137c95/
U2 - 10.1016/j.ejmech.2025.118124
DO - 10.1016/j.ejmech.2025.118124
M3 - Article
C2 - 40946533
VL - 300
SP - 118124
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 118124
ER -
ID: 69742841