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
{"title":"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","authors":"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","doi":"10.1016/j.steroids.2025.109638","DOIUrl":null,"url":null,"abstract":"<div><div>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 <img>N<img>C<img>S 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)<sub>2</sub>-NaN<sub>3</sub> 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)H<sub>2</sub> 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).</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"220 ","pages":"Article 109638"},"PeriodicalIF":2.1000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"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\",\"doi\":\"10.1016/j.steroids.2025.109638\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <img>N<img>C<img>S 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)<sub>2</sub>-NaN<sub>3</sub> 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)H<sub>2</sub> 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).</div></div>\",\"PeriodicalId\":21997,\"journal\":{\"name\":\"Steroids\",\"volume\":\"220 \",\"pages\":\"Article 109638\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2025-05-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Steroids\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0039128X25000790\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Steroids","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0039128X25000790","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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).
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.