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Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro. / Pronina, Anastasia A.; Shcherbakov, Dmitriy N.; Sanchez-Pimentel, Artem P. et al.

In: Bioorganic Chemistry, Vol. 181, 2026.

Research output: Contribution to journal › Article › peer-review

Harvard

Pronina, AA, Shcherbakov, DN, Sanchez-Pimentel, AP, Nikitina, EV, Zubkov, FI, Meshkova, YV, Marenina, MK, Maltsev, NV, Belenkaya, SV, Trufanov, VO, Volosnikova, EA, Zaykovskay, AV, Borisevich, SS, Khamitov, EM, Baev, DS, Mustaev, EA, Fedorov, AY, Arkhipov, SG, Vlaskina, AV, Nemchinova, AR, Samygina, VR, Pyankov, OV, Yarovaya, O, Xu, W, Salakhutdinov, NF & Khvostov, MV 2026, 'Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro', Bioorganic Chemistry, vol. 181. https://doi.org/10.1016/j.bioorg.2026.110402

APA

Pronina, A. A., Shcherbakov, D. N., Sanchez-Pimentel, A. P., Nikitina, E. V., Zubkov, F. I., Meshkova, Y. V., Marenina, M. K., Maltsev, N. V., Belenkaya, S. V., Trufanov, V. O., Volosnikova, E. A., Zaykovskay, A. V., Borisevich, S. S., Khamitov, E. M., Baev, D. S., Mustaev, E. A., Fedorov, A. Y., Arkhipov, S. G., Vlaskina, A. V., ... Khvostov, M. V. (2026). Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro. Bioorganic Chemistry, 181. https://doi.org/10.1016/j.bioorg.2026.110402

Vancouver

Pronina AA, Shcherbakov DN, Sanchez-Pimentel AP, Nikitina EV, Zubkov FI, Meshkova YV et al. Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro. Bioorganic Chemistry. 2026;181. doi: 10.1016/j.bioorg.2026.110402

Author

Pronina, Anastasia A. ; Shcherbakov, Dmitriy N. ; Sanchez-Pimentel, Artem P. et al. / Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro. In: Bioorganic Chemistry. 2026 ; Vol. 181.

BibTeX

@article{89e18fd7bdea408baf3ac35e7de92773,
title = "Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro",
abstract = "This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf , exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.",
keywords = "Coronaviruses, Inhibition, Main viral protease, Molecular docking, SARS-CoV-2, Tetrahydroquinoline",
author = "Pronina, {Anastasia A.} and Shcherbakov, {Dmitriy N.} and Sanchez-Pimentel, {Artem P.} and Nikitina, {Eugeniya V.} and Zubkov, {Fedor I.} and Meshkova, {Yulia V.} and Marenina, {Mariya K.} and Maltsev, {Nikolay V.} and Belenkaya, {Svetlana V.} and Trufanov, {Vadim O.} and Volosnikova, {Ekaterina A.} and Zaykovskay, {Anna V.} and Borisevich, {Sophia S.} and Khamitov, {Edward M.} and Baev, {Dmitriy S.} and Mustaev, {Egor A.} and Fedorov, {Alexey Yu} and Arkhipov, {Sergey G.} and Vlaskina, {Anna V.} and Nemchinova, {Anastasia R.} and Samygina, {Valeriya R.} and Pyankov, {Oleg V.} and Olga Yarovaya and Wei Xu and Salakhutdinov, {Nariman F.} and Khvostov, {Mikhail V.}",
year = "2026",
doi = "10.1016/j.bioorg.2026.110402",
language = "English",
volume = "181",
journal = "Bioorganic Chemistry",
issn = "0045-2068",
publisher = "Elsevier Science Publishing Company, Inc.",

}

RIS

TY - JOUR

T1 - Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro

AU - Pronina, Anastasia A.

AU - Shcherbakov, Dmitriy N.

AU - Sanchez-Pimentel, Artem P.

AU - Nikitina, Eugeniya V.

AU - Zubkov, Fedor I.

AU - Meshkova, Yulia V.

AU - Marenina, Mariya K.

AU - Maltsev, Nikolay V.

AU - Belenkaya, Svetlana V.

AU - Trufanov, Vadim O.

AU - Volosnikova, Ekaterina A.

AU - Zaykovskay, Anna V.

AU - Borisevich, Sophia S.

AU - Khamitov, Edward M.

AU - Baev, Dmitriy S.

AU - Mustaev, Egor A.

AU - Fedorov, Alexey Yu

AU - Arkhipov, Sergey G.

AU - Vlaskina, Anna V.

AU - Nemchinova, Anastasia R.

AU - Samygina, Valeriya R.

AU - Pyankov, Oleg V.

AU - Yarovaya, Olga

AU - Xu, Wei

AU - Salakhutdinov, Nariman F.

AU - Khvostov, Mikhail V.

PY - 2026

Y1 - 2026

N2 - This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf , exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.

AB - This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf , exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.

KW - Coronaviruses

KW - Inhibition

KW - Main viral protease

KW - Molecular docking

KW - SARS-CoV-2

KW - Tetrahydroquinoline

UR - https://www.scopus.com/pages/publications/105048566383

UR - https://www.mendeley.com/catalogue/b1b19045-61ef-302b-9714-2258748d8a72/

U2 - 10.1016/j.bioorg.2026.110402

DO - 10.1016/j.bioorg.2026.110402

M3 - Article

C2 - 42673845

VL - 181

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

ER -

ID: 85071033