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. 2023 Jun 28;24(13):10758.
doi: 10.3390/ijms241310758.

3-[ N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

Kseniya N Sedenkova  1 , Artem S Sazonov  1 , Dmitry A Vasilenko  1 , Kristian S Andriasov  1 , Marina G Eremenko  1 , Yuri K Grishin  1 , Evgeny V Khvatov  2 , Alexander S Goryashchenko  2 , Victoria I Uvarova  2 , Dmitry I Osolodkin  2   3 , Aydar A Ishmukhametov  2   3 , Elena B Averina  1
Affiliations

3-[ N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

Kseniya N Sedenkova et al. Int J Mol Sci. .

Abstract

Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses. The structural analogs of spirocyclic compounds with a single sulfonyl group or 1,2-annulated cyclooctane ring were also investigated. Almost all the studied 3-[N,N-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing p-nitrophenyl groups in the sulfonyl part (EC50 2.0 ± 0.5 μM), while the highest potency against WNV was found for the compounds with lipophilic substituents in sulfonyl moiety, naphtyl being the most favorable one (EC50 1.3 ± 0.5 μM). In summary, two novel scaffolds of anti-flaviviral agents based on N,N-bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV.

Keywords: 1,2-annulated compounds; West Nile virus; antivirals; isoxazolines; spiro-compounds; sulfonylation; tick-borne encephalitis virus; yellow fever virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of approved drugs, natural and bioactive compounds with spirocyclic motifs, medium rings, isoxazoline moieties, and their combinations.
Figure 2
Figure 2
Previously obtained aminoisoxazoline derivatives 1–3 [26].
Figure 3
Figure 3
Examples of compounds with antiviral activity against TBEV, YFV, WNV, and DENV [31,32,33,35,39].
Figure 4
Figure 4
Structures of 3-[N,N-bis(sulfonyl)amino]isoxazolines 4,5, investigated in the present work, and previously studied isoxazole derivative 6 that was used as a positive control [41].
See this image and copyright information in PMC

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