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In Vitro Antiviral Activity of a New Indol-3-carboxylic Acid Derivative Against SARS-CoV-2

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1. Title Title of document In Vitro Antiviral Activity of a New Indol-3-carboxylic Acid Derivative Against SARS-CoV-2
2. Creator Author's name, affiliation, country A. N. Narovlyansky; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country M. V. Filimonova; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country N. G. Tsyshkova; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country A. V. Pronin; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country T. V. Grebennikova; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country E. V. Karamov; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country V. F. Larichev; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country G. V. Kornilayeva; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country I. T. Fedyakina; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country I. V. Dolzhikova; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country M. V. Mezentseva; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country E. I. Isaeva; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country V. V. Poloskov; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country L. S. Koval; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country V. P. Marinchenko; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country V. I. Surinova; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country A. S. Filimonov; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country A. A. Shitova; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country O. V. Soldatova; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country A. V. Sanin; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country I. K. Zubashev; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country A. V. Ponomarev; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation
; Россия
2. Creator Author's name, affiliation, country V. V. Veselovsky; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
; Россия
2. Creator Author's name, affiliation, country V. V. Kozlov; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation; Gamasintez LLC ; Россия
2. Creator Author's name, affiliation, country A. V. Stepanov; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences ; Россия
2. Creator Author's name, affiliation, country A. V. Khomich; Gamasintez LLC
; Россия
2. Creator Author's name, affiliation, country V. S. Kozlov; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country S. A. Ivanov; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country P. V. Shegai; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country A. D. Kaprin; National Medical Research Center for Radiology, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country F. I. Ershov; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
2. Creator Author's name, affiliation, country A. L. Gintsburg; National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya, Ministry of Health of the Russian Federation ; Россия
3. Subject Discipline(s)
3. Subject Keyword(s) SARS-CoV-2; indole-3 carboxylic acid derivative; antiviral activity; cell culture
4. Description Abstract

The coronavirus disease (COVID-19) pandemic has brought into sharp relief the threat posed by coronaviruses and laid the foundation for a fundamental analysis of this viral family, as well as a search for effective anti-COVID drugs. Work is underway to update existent vaccines against COVID-19, and screening for low-molecular-weight anti-COVID drug candidates for outpatient medicine continues. The opportunities and ways to accelerate the development of antiviral drugs against other pathogens are being discussed in the context of preparing for the next pandemic. In 2012–2015, Tsyshkova et al. synthesized a group of water-soluble low-molecular-weight compounds exhibiting an antiviral activity, whose chemical structure was similar to that of arbidol. Among those, there were a number of water-soluble compounds based on 5-methoxyindole-3-carboxylic acid aminoalkyl esters. Only one member of this rather extensive group of compounds, dihydrochloride of 6-bromo-5-methoxy-1-methyl-2-(1-piperidinomethyl)-3-(2-diethylaminoethoxy)carbonylindole, exhibited a reliable antiviral effect against SARS-CoV-2 in vitro. At a concentration of 52.0 μM, this compound completely inhibited the replication of the SARS-CoV-2 virus with an infectious activity of 106 TCID50/mL. The concentration curves of the analyzed compound indicate the specificity of its action. Interferon-inducing activity, as well as suppression of syncytium formation induced by the spike protein (S-glycoprotein) of SARS-CoV-2 by 89%, were also revealed. In view of its synthetic accessibility − high activity (IC50 = 1.06 µg/mL) and high selectivity index (SI = 78.6) − this compound appears to meets the requirements for the development of antiviral drugs for COVID-19 prevention and treatment.

5. Publisher Organizing agency, location Acta Naturae Ltd
6. Contributor Sponsor(s) Ministry of Health of the Russian Federation (056-00119-21-00)
7. Date (DD-MM-YYYY) 17.01.2024
8. Type Status & genre Peer-reviewed Article
8. Type Type Research Article
9. Format File format
10. Identifier Uniform Resource Identifier https://actanaturae.ru/2075-8251/article/view/26623
10. Identifier Digital Object Identifier (DOI) 10.32607/actanaturae.26623
11. Source Title; vol., no. (year) Acta Naturae; Vol 15, No 4 (2023)
12. Language English=en en
13. Relation Supp. Files Fig. 1. 6-Bromo-1-methyl-5-methoxy-2-(1-piperidinomethyl)-3-(2-diethylamino ethoxy)carbonylindole dihydrochloride (compound 1) (53KB) doi: 10.32607/20758251-2023-15-4-83-91-130344
Fig. 2. Reagents and conditions: a. (1) aq. NaOH, dioxane; (2) Me2SO4, 20°C; b. N-bromosuccinimide, CCl4, boiling; c. N-bromosuccinimide, (PhCOO)2, CCl4, irradiation (100 W bulb), boiling; d. piperidine, PhH, 20°C; e. (1) aq. NaOH, EtOH, boiling; (2) HCl (conc.); f. SOCl2, dioxane, DMFA (cat.), 60°C; g. (1) Et2NCH2CH2OH, Et3N, PhH, boil.; (2) HCl, Et2O, acetone, 20°C (361KB) doi: 10.32607/20758251-2023-15-4-83-91-130345
Fig. 3. IR spectrum of compound 1 (134KB) doi: 10.32607/20758251-2023-15-4-83-91-130346
Fig. 4. 1H NMR spectrum of compound 1 (113KB) doi: 10.32607/20758251-2023-15-4-83-91-130347
Fig. 5. Mass spectrum of compound 1 (98KB) doi: 10.32607/20758251-2023-15-4-83-91-130348
Fig. 6. Determining the cytotoxic effect of compound 1 96 h after its addition to the Vero E6 cell culture (using MTS vital dye). СС50 = 83.32 µg/mL (114KB) doi: 10.32607/20758251-2023-15-4-83-91-130349
14. Coverage Geo-spatial location, chronological period, research sample (gender, age, etc.)
15. Rights Copyright and permissions Copyright (c) 2024 Narovlyansky A.N., Filimonova M.V., Tsyshkova N.G., Pronin A.V., Grebennikova T.V., Karamov E.V., Larichev V.V., Kornilayeva G.V., Fedyakina I.T., Dolzhikova I.V., Mezentseva M.V., Isaeva E.I., Poloskov V.V., Koval L.S., Marinchenko V.P., Surinova V.I., Filimonov A.S., Shitova A.A., Soldatova O.V., Sanin A.V., Zubashev I.K., Ponomarev A.V., Veselovsky V.V., Kozlov V.V., Stepanov A.V., Khomich A.V., Kozlov V.S., Ivanov S.A., Shegai P.V., Kaprin A.D., Ershov F.I., Gintsburg A.L.
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