5-氨基-1,2,3,4-噻唑、1-四唑-5-硫酮和1-四唑-5-胺杂交种及其对SARS-CoV-2主要蛋白酶抑制作用的研究

IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sergey A. Popov , Elvira E. Shults , Dmitry S. Baev , Varvara Yu. Chirkova , Ekaterina A. Volosnikova , Svetlana V. Belenkaya , Dmitry N. Shcherbakov , Mikhail.A. Pokrovsky , Mohammad S. Hamad , Andrey G. Pokrovsky
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引用次数: 0

摘要

制备了5-氨基-1,2,3,4-噻唑、1-四唑-5-硫酮和1-四唑-5-胺的新杂环熊酮和28-异熊酮杂环衍生物。在离五环主链不同距离上含有NCS基团的三萜类化合物与水合肼反应可得到熊衍生的肼碳硫酰胺。随后的亚硝化得到了5-氨基-1,2,3,4-噻唑的萜类衍生物。在Hg(OAc)2-NaN3的作用下,氨基硫脲与3β-乙酰氧基-12-烯-28-基取代基杂环化,得到1-四唑-5-胺杂化物。通过叠氮化钠与异硫氰酸三萜偶联,制备了与三萜骨架不同杂环位置的1-四唑-5-硫酮。研究了新的杂环衍生物作为SARS-CoV-2 3CLpro抑制剂的活性。对三萜的1-四唑-5-硫酮杂交体有明显的抑制作用。在所研究的化合物中,活性最高的化合物是在骨架的C(28)H2基团上结合了1-四唑-5-硫酮片段,在3位上有一个游离OH基团。分子对接通过催化剂Cys145的巯基和新杂化化合物的四唑杂环之间形成二硫键来假设3CLpro的共价结合。三萜骨架提供了多个外部疏水接触,这对配合物的稳定性至关重要。结果表明杂环硫酮杂合体作为靶向3CLpro蛋白酶(3-凝乳胰蛋白酶样蛋白酶)的非拟肽共价抑制剂的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ursane hybrids with 5-amino-1,2,3,4-thiatriazole, 1-tetrazole-5-thione, and 1-tetrazole-5-amines and study of their inhibition of main SARS-CoV-2 protease
A series of new heterocyclic ursane and 28-norursane hybrids − derivatives of 5-amino-1,2,3,4-thiatriazole, 1-tetrazole–5-thione, and 1-tetrazole–5-amines were prepared. Reacting triterpenoids holding NCS groups at different distances from the pentacyclic backbone with hydrazine hydrate resulted in ursane-derived hydrazinecarbothioamides. Subsequent nitrosation afforded terpenoid derivatives of 5-amino-1,2,3,4-thiatriazole. Heterocyclization of amino-thioureas with 3β-acetoxyurs-12-en-28-yl substituent under the action of Hg(OAc)2-NaN3 led to hybrids of 1-tetrazole–5-amines. 1-Tetrazole–5-thiones with different positions of heterocycle relative to the triterpene skeleton were prepared by coupling sodium azide with triterpene isothiocyanates. The activity of the new heterocyclic derivatives as inhibitors of 3CLpro of SARS-CoV-2 was investigated. Remarkable inhibition was observed for the 1-tetrazole-5-thione hybrids of triterpenoids. The highest activity among the studied compounds was provided by the combination of a 1-tetrazole-5-thione moiety at the C(28)H2 group of the ursane frame having a free OH group at the 3-position. Molecular docking assumed the covalent binding of 3CLpro via the formation of a disulfide bond between the thiol groups of the catalytic Cys145 and the tetrazole heterocycle of the new hybrid compounds. The triterpenoid backbone provided multiple external hydrophobic contacts essential for the stability of the complex. The results demonstrate the potential of heterocyclic thione hybrids as non-peptidomimetic covalent inhibitors targeting 3CLpro protease (3-Chymotrypsin-like Protease).
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来源期刊
Steroids
Steroids 医学-内分泌学与代谢
CiteScore
5.10
自引率
3.70%
发文量
120
审稿时长
73 days
期刊介绍: STEROIDS is an international research journal devoted to studies on all chemical and biological aspects of steroidal moieties. The journal focuses on both experimental and theoretical studies on the biology, chemistry, biosynthesis, metabolism, molecular biology, physiology and pharmacology of steroids and other molecules that target or regulate steroid receptors. Manuscripts presenting clinical research related to steroids, steroid drug development, comparative endocrinology of steroid hormones, investigations on the mechanism of steroid action and steroid chemistry are all appropriate for submission for peer review. STEROIDS publishes both original research and timely reviews. For details concerning the preparation of manuscripts see Instructions to Authors, which is published in each issue of the journal.
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