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

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.

Figure 1

Examples of approved drugs, natural and bioactive compounds with spirocyclic motifs, medium rings, isoxazoline moieties, and their combinations.

Figure 2

Previously obtained aminoisoxazoline derivatives 1–3 [26].

Figure 3

Examples of compounds with antiviral activity against TBEV, YFV, WNV, and DENV [31,32,33,35,39].

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].