Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.
FSASI "Chumakov FSC R&D IBP RAS" (Institute of Poliomyelitis), Moscow 108819, Russia.
Int J Mol Sci. 2023 Jun 28;24(13):10758. doi: 10.3390/ijms241310758.
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-[-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-[-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing -nitrophenyl groups in the sulfonyl part (EC 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 (EC 1.3 ± 0.5 μM). In summary, two novel scaffolds of anti-flaviviral agents based on -bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV.
含杂环部分的螺环化合物是现代药物设计有前途的 3D 支架。在寻找新型抗黄病毒药物的过程中，我们获得了一系列含有螺环稠合环辛烷环的 3-[-双（磺酰基）氨基]异恶唑啉，并评估了它们对 tick-borne encephalitis（TBEV）、yellow fever（YFV）和 West Nile（WNV）病毒的抗病毒活性。还研究了具有单个磺酰基或 1,2-稠合环辛烷环的螺环化合物的结构类似物。几乎所有研究的 3-[-双（磺酰基）氨基]异恶唑啉都显示出对 TBEV 和 WNV 的抗病毒活性。磺酰基部分含有 -硝基苯基的螺异恶唑啉衍生物对 TBEV 的活性最高（EC 2.0 ± 0.5 μM），而对 WNV 活性最高的化合物是磺酰基部分具有亲脂性取代基的化合物，其中萘基最有利（EC 1.3 ± 0.5 μM）。总之，提出了两种基于 -双（磺酰基）氨基]异恶唑啉的抗黄病毒药物的新骨架，这类化合物对 TBEV 和 WNV 表现出活性。
