TY - JOUR

T1 - 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

AU - Popov, Sergey A.

AU - Shults, Elvira E.

AU - Baev, Dmitry S.

AU - Chirkova, Varvara Yu

AU - Volosnikova, Ekaterina A.

AU - Belenkaya, Svetlana V.

AU - Shcherbakov, Dmitry N.

AU - Pokrovsky, Mikhail A.

AU - Hamad, Mohammad S.

AU - Pokrovsky, Andrey G.

N1 - This work was supported by Russian Science Foundation (grant # 23-73-00077). Analytical and spectroscopic studies were performed at the Chemical Service collective Center of SB RAS.

PY - 2025/8

Y1 - 2025/8

N2 - 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 [sbnd]N[dbnd]C[dbnd]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)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).

AB - 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 [sbnd]N[dbnd]C[dbnd]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)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).

KW - Covalent bonding

KW - Molecular docking

KW - SARS-CoV-2 protease

KW - Tetrazole

KW - Thione

KW - Ursane hybrid

UR - https://www.mendeley.com/catalogue/aaf39cb7-567e-389f-bed2-b6292c7cf09d/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-105005873145&origin=inward&txGid=a47dd65cb11640328d25a9419a5182bb

U2 - 10.1016/j.steroids.2025.109638

DO - 10.1016/j.steroids.2025.109638

M3 - Article

C2 - 40409429

VL - 220

JO - Steroids

JF - Steroids

SN - 0039-128X

M1 - 109638

ER -