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.

[3+2] Cycloaddition of N‐benzylazomethine Methylide with Various Arylidene‐Azolones

“…There are two general approaches to N-benzyl-1-(trimethylsilyl)-N-(methoxymethyl)methanamine I activation for corresponding yilde cycloaddition, presented in the literature. [16,28,29] This ylide can be generated either by heating with lithium fluoride in dimethyl formamide or by the action of trifluoroacetic acid in THF at room temperature. Examination of the conditions applied to azolones 1-4 e demonstrated that the use of TFA is typically more effective.…”

“…[6,7] In particular, various spirocyclic derivatives incorporating five-membered heterocyclic core are of interest, since their synthetic and natural analogs exhibit a wide range of pharmacological activities, including antimicrobial, antiviral, fungicidal, antidiabetic, anticonvulsant, antitumor and other effects (Scheme 1). [8][9][10][11][12][13][14][15][16][17][18] Many methods have been developed for the synthesis of such substances. Among all of them, cycloaddition reactions occupy an important method.…”

Phenotypic assessment of antiviral activity for spiro‐annulated oxepanes and azepenes

“…These substituents can be decorated further to construct more promising molecules, given the prevalence of piperidines in approved drugs (Vitaku et al, 2014). Molecules with the triazole ring were slightly more potent, especially when an aromatic substituent was introduced into the triazole ring (1, 2, 4, 5, 10, 11) instead of carboxymethyl (3,6,12); all the carboxymethyl bearing compounds were in fact inactive. Effect of fluorination of the distal phenyl could not be established due to a high standard deviation of EC 50 for compound 2.…”