Structure-Based Design, Synthesis, and Biological Evaluation of the Cage-Amide Derived Orthopox Virus Replication Inhibitors

Evgenii S Mozhaitsev; Evgeniy V Suslov; Daria A Rastrepaeva; Olga I Yarovaya; Sophia S Borisevich; Edward M Khamitov; Dmitry S Kolybalov; Sergey G Arkhipov; Nikolai I Bormotov; Larisa N Shishkina; Olga A Serova; Roman V Brunilin; Andrey A Vernigora; Maxim B Nawrozkij; Alexander P Agafonov; Rinat A Maksyutov; Konstantin P Volcho; Nariman F Salakhutdinov

doi:10.3390/v15010029

Structure-Based Design, Synthesis, and Biological Evaluation of the Cage-Amide Derived Orthopox Virus Replication Inhibitors

Viruses. 2022 Dec 21;15(1):29. doi: 10.3390/v15010029.

Authors

Evgenii S Mozhaitsev¹, Evgeniy V Suslov¹, Daria A Rastrepaeva¹, Olga I Yarovaya¹, Sophia S Borisevich², Edward M Khamitov², Dmitry S Kolybalov^{3

4}, Sergey G Arkhipov^{3

4}, Nikolai I Bormotov⁵, Larisa N Shishkina⁵, Olga A Serova⁵, Roman V Brunilin⁶, Andrey A Vernigora⁶, Maxim B Nawrozkij⁷, Alexander P Agafonov⁵, Rinat A Maksyutov⁵, Konstantin P Volcho¹, Nariman F Salakhutdinov¹

Affiliations

¹ Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Lavrentyev Ave. 9, 630090 Novosibirsk, Russia.
² Laboratory of Chemical Physics, Laboratory of Physical and Chemical Methods of Analysis, Ufa Institute of Chemistry Ufa Federal Research Center, 71 Pr. Oktyabrya, 450078 Ufa, Russia.
³ Synchrotron Radiation Facility SKIF, G.K. Boreskov Institute of Catalysis SB RAS, 630559 Koltsovo, Russia.
⁴ Scientific Educational Center "Institute of Chemical Technology", Novosibirsk State University, 630090 Novosibirsk, Russia.
⁵ State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia.
⁶ Department of Analytical, Physical Chemistry and Polymer Chemistry and Physics, Department of Organic Chemistry, Volgograd State Technical University Lenina, Avenue 28, 400005 Volgograd, Russia.
⁷ Center of Translational Medicine, Sirius University of Science and Technology, Olympic Avenue 1, Krasnodar Krai, 354340 Sirius, Russia.

Abstract

Despite the fact that the variola virus is considered eradicated, the search for new small molecules with activity against orthopoxviruses remains an important task, especially in the context of recent outbreaks of monkeypox. As a result of this work, a number of amides of benzoic acids containing an adamantane fragment were obtained. Most of the compounds demonstrated activity against vaccinia virus, with a selectivity index SI = 18,214 for the leader compound 18a. The obtained derivatives also demonstrated activity against murine pox (250 ≤ SI ≤ 6071) and cowpox (125 ≤ SI ≤ 3036). A correlation was obtained between the IC₅₀ meanings and the binding energy to the assumed biological target, the p37 viral protein with R² = 0.60.

Keywords: adamantane; amides; antipox activity; p37.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / pharmacology
Animals
Communicable Diseases*
Mice
Orthopoxvirus*
Vaccinia virus
Variola virus*
Virus Replication

Substances

Amides

Grants and funding

Synthesis of compounds supported by the Russian Ministry of Education and Science No. 1021052605829-1-1.4.1. Biological testing in the orthopoxviruses has been carried out with the State assignment of the State Research Centre of Virology and Biotechnology VECTOR. Crystallographic research and molecular modeling were supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2021-1355 dated 12 October 2021) as part of the implementation of certain activities of the Federal Scientific and Technical Program for the Development of Synchrotron and Neutron Research and Research Infrastructure for 2019–2027.