Borneol Ester Derivatives as Entry Inhibitors of a Wide Spectrum of SARS-CoV-2 Viruses

Abstract

In the present work we studied the antiviral activity of the home library of monoterpenoid derivatives using the pseudoviral systems of our development, which have glycoproteins of the SARS-CoV-2 virus strains Wuhan and Delta on their surface. We found that borneol derivatives with a tertiary nitrogen atom can exhibit activity at the early stages of viral replication. In order to search for potential binding sites of ligands with glycoprotein, we carried out additional biological tests to study the inhibition of the re-receptor-binding domain of protein S. For the compounds that showed activity on the pseudoviral system, a study using three strains of the infectious SARS-CoV-2 virus was carried out. As a result, two leader compounds were found that showed activity on the Wuhan, Delta, and Omicron strains. Based on the biological results, we searched for the potential binding site of the leader compounds using molecular dynamics and molecular docking methods. We suggested that the compounds can bind in conserved regions of the central helices and/or heptad repeats of glycoprotein S of SARS-CoV-2 viruses.

(+)-Usnic Acid and Its Derivatives as Inhibitors of a Wide Spectrum of SARS-CoV-2 Viruses

“…To find out whether the usnic acid derivatives are virus entry inhibitors, additionally synthesized compounds were tested in a neutralization assay using pseudoviruses bearing S glycoprotein S of the SARS-CoV-2 virus on their surface. In this study, HEK293T-hAce2-TMPRSS2 (transient) cell lines were used according to the methodology described in [ 56 ]. We used Arbidol as a reference drug.…”

Synthesis and Antiviral Properties of Camphor-Derived Iminothiazolidine-4-Ones and 2,3-Dihydrothiazoles

“…Many different classes of camphor-based derivatives have been synthesized with a wide range of antiviral properties. We have previously shown that derivatives with a 1,7,7-trimethylbicyclo[2.2.1]heptane backbone exhibit a wide spectrum of antiviral activity against influenza [ 7 , 8 ], hantaviruses [ 9 ], filoviruses [ 10 , 11 , 12 ], orthopoxviruses [ 13 , 14 ] and SARS-CoV-2 [ 15 ]. Some compounds, with a heterocyclic fragment synthesized previously on the basis of camphor and borneol, which have shown significant antiviral properties, are presented in Figure 1 .…”

Synthesis of N-heterocyclic amides based on (+)-camphoric acid and study of their antiviral activity and pharmacokinetics

“…9 The signifi cant library of the ester derivatives based on natural alcohol (-)-borneol containing N-heterocyclic fragments is characterized by a broad range of antiviral activity: the compounds are active against infl uenza viruses, 10 Ebola virus, 11 Marburg virus, 12 respiratory syncytial virus, 13 and Orthopoxviruses, 14 including smallpox virus, 15 and are entry inhibitors of the SARS-CoV-2 virus. 16 Ethers bearing bicyclobornane framework and N-heterocyclic fragments also have a wide range of antiviral activity. 17 (1R,3S)-(+)-Camphoric acid ( 1) is an available commercial compound and can be synthesized by the exhaustive oxidation of natural (+)-camphor.…”

“…)), 21.4 (C(7)), 22.2 (C(8)), 27.5 (C(4)), 34.5 (C(5)), 47.1 (C(2)), 52.1, 52.8, 52.9, 53.2, 53.3 (C(13), С(14), С(15), С(16), С(17), С(18), С(19), С(20)); 54.7 (С(3)), 61.4 (С(12)), 62.0 (С(11)), 62.5 (С(1)), 169.2 and 169.7 (С(9), С(10)). HR MS: found m/z 450.3680 [M] + ; calculated for C 24 H 46 N 6 (4j).…”

“…HR MS: found m/z 538.3478 [M] + ; calculated for C 26 H 46 N 6 O 6 + 538.3473.N,N´-((1R,3S)-1,2,2-Trimethylcyclopentane-1,3-diyl)bis[2-(4-phenylpiperazin-1-yl)acetamide] (4k).The yield was 0.57 g (61%), brown oily substance; [α] D 23 = +3.3 (EtOH) 1. H NMR, δ: 0.87 (s, 3 H, C(6)H 3 ); 1.00 (s, 3 H, C(7)H 3 ); 1.43 (s, 3 H, C(8)H 3 ); 1.99-2.28 (m, 4 Н, Н(5 ax ), Н(5 eq ), Н(4 ax ), Н(4 eq )); 2.68-2.78 (m, 8 Н, Н(13), Н(16), Н(17), Н(19)); 3.02 (d, 2 Н, H(11), J = 4.0 Hz); 3.11 (d, 2 Н, Н(12), J = 10.6 Hz); 3.19-3.27 (m, 8 Н, H(14), Н(15), Н(18), Н(20)); 4.30-4.37 (m, 1 Н, Н(3)); 6.88-6.92 (m, 2 Н, Н(25), Н(30)); 6.93-6.96 (m, 4 Н, Н(23), Н(27), Н(28), Н(32)); 7.23 (d, 1 Н, NH, J = 9.9 Hz); 7.28-7.32 (m, 4 Н, H(24), Н(26), Н(29), Н(31)); 7.44 (br.s, 1 Н, NH) 13. C NMR, δ: 18.0 (C(6)), 21.3 (C(7)), 22.2 (C(8)), 27.4 (C(4)), 34.7 (C(5)), 47.0 (C(2)), 49.3 and 49.4 (С(14), С(15) and С(18), С(20)), 53.3 and 53.4 (С(13), С(16) and С(17), С(19)), 54.6 (С(3)), 61.4 (С(12)), 62.0 (С(11)), 62.4 (С(1)), 115.9 and 116.0 (С(23), С(27) and С(28), С(32)), 120.0 (С(25), С(30)), 129.0 (С(29), С(31), С(24), С(26)), 150.8 (С(21), С(22)), 168.9 and 169.4 (С(9), С(10)).…”