Synlett 2022; 33(05): 458-463
DOI: 10.1055/a-1582-0243
cluster
Design and Chemical Synthesis of Antivirals

De novo Design of SARS-CoV-2 Main Protease Inhibitors

a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
b   Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstrasse 5-13, 81377 München, Germany
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
Jessica N. Spradlin
c   Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, 94720, USA
,
Dustin Dovala
d   Novartis Institutes for BioMedical Research, Emeryville, CA, 94608, USA
,
c   Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, 94720, USA
,
Yingkai Zhang
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
Dirk Trauner
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
› Author Affiliations
D.T. and his group are thankful for the COVID-19 Catalyst Grant by the New York University (NYU). Y.Z. would like to acknowledge the support by the National Institutes of Health (NIH, Grant No. R35 GM127040). C.F. thanks the Swiss National Science Foundation (SNSF, Grant No. 178569) for a postdoctoral fellowship. N.A.V. thanks the Studienstiftung des Deutschen Volkes (German Academic Scholarship Foundation) for a PhD Fellowship. Z.P. and K.P.R. are supported by the New York University (NYU) MacCracken Fellowship.


Abstract

The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, MPro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar noncovalent inhibitors of the viral main protease.

Supporting Information



Publication History

Received: 13 July 2021

Accepted after revision: 10 August 2021

Accepted Manuscript online:
10 August 2021

Article published online:
05 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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  • 12 Procedures a-d for the synthesis of compound 28: (a) To a mixture of 5‑bromo-2-hydroxypyridine (25) (522 mg, 3.00 mmol), K2CO3 (1.24 g, 9.00 mmol) in acetone (30 mL) was added 2-chloro-N-cyclohexylacetamide (5a) (738 mg, 4.20 mmol) at room temperature and the mixture was stirred at 50 °C for 18 hours. The suspension was treated with hexanes (50 mL), filtered and washed portionwisely with water (100 mL). The remaining solid was dried and recrystallized from acetone/hexanes to give intermediate 26 as an off-white solid (716 mg, 76%): R f 0.31 (hexanes:EtOAc, 1:2); 1H-NMR (400 MHz, CDCl3): δ = 7.56 (1H, d, 4 J 2.6 Hz), 7.41 (1H, dd, 3 J 9.7 Hz, 4 J 2.7 Hz), 6.62 (1H, d, 3 J 5.8 Hz), 6.52 (1H, d, 3 J 9.7 Hz), 4.45 (2H, s), 3.65–3.74 (1H, m), 1.83–1.87 (2H, m), 1.65–1.71 (2H, m), 1.54–1.61 (1H, m), 1.28–1.39 (2H, m), 1.11–1.21 (3H, m); 13C‑NMR (101 MHz, CDCl3): δ = 165.6, 161.4, 143.7, 138.1, 121.9, 99.0, 54.0, 48.8, 32.8, 25.6, 24.7; APCI-HRMS: m/z calcd. for [C13H18BrN2O2]+ 315.0526 found 315.0529 [M+H]+. (b) A mixture of intermediate 26 (94.0 mg, 0.300 mmol), 4-fluorophenylboronic acid (105 mg, 0.750 mmol), Na2CO3 (127 mg, 1.20 mmol), Pd(PPh3)4 (17.3 mg, 15.0 µmol, 5.00 mol%) was evacuated for 10 minutes under high vacuum and backfilled with N2at room temperature. The mixture was treated with PhMe:EtOH:H2O (1.9 mL, 0.74 mL, 0.26 mL) and stirred at 75 °C for 3 hours in a pre-heated sand bath. The mixture was treated with water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Precipitation from hexanes gives intermediate 27 as a white solid (85.3 mg, 87%): R f 0.26 (hexanes:EtOAc, 1:2, UV); 1H-NMR (400 MHz, CDCl3): δ = 7.64 (1H, dd, 3 J 9.4 Hz, 4 J 2.6 Hz), 7.59 (1H, d, 4 J 2.4 Hz), 7.36–7.40 (2H, m), 7.09–7.13 (2H, m), 6.82 (1H, d, 3 J 6.7 Hz), 6.71 (1H, d, 3 J 9.4 Hz), 4.57 (2H, s), 3.67–3.76 (1H, m), 1.85–1.89 (2H, m), 1.66–1.71 (2H, m), 1.55–1.60 (1H, m), 1.28–1.36 (2H, m), 1.14–1.24 (3H, m); 13C‑NMR (101 MHz, CDCl3): δ = 166.1, 162.6 (1 J CF 247 Hz), 162.2, 140.4, 135.4, 132.3 (4 J CF 3.7 Hz), 127.8 (3 J CF 8.1 Hz), 120.9, 120.5, 116.2 (2 J CF 22 Hz), 54.6, 48.7, 32.8, 25.6, 24.7; 19F-NMR (377 MHz, CDCl3): δ = –114.66; APCI-HRMS: m/z calcd. for [C19H22FN2O2]+ 329.1660 found 329.1660 [M+H]+. (c) To a solution of intermediate 27 (32.8 mg, 0.100 mmol) in glacial acetic acid (1.0 mL) was added dropwise bromine (8.00 µL, 0.150 mmol) at room temperature. The orange mixture was stirred at 60 °C for 18 hours. When cooled to room temperature the mixture was treated with aqueous saturated Na2S2O3 and adjusted to pH 7 with aqueous saturated NaHCO3. The suspension was filtered and washed extensively with water. The filter cake was dried in vacuo and purified by column chromatography over silica gel with eluent 100% hexanes to hexanes:EtOAc 90:10 to 75:25 to 60:40 to 50:50 to give 2-(3-bromo-5-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl)-N-cyclohexyl­acetamide (27.0 mg, 66%): R f 0.30 (hexanes:EtOAc, 1:1, UV); 1H‑NMR (400 MHz, CDCl3): δ = 8.03 (1H, d, 4 J 2.4 Hz), 7.64 (1H, d, 4 J 2.3 Hz), 7.36–7.39 (2H, m), 7.09–7.13 (2H, m), 6.73 (1H, d, 3 J 8.1 Hz), 4.63 (2H, s), 3.67–3.76 (1H, m), 1.85–1.89 (2H, m), 1.67–1.72 (2H, m), 1.56–1.61 (1H, m), 1.28–1.38 (2H, m), 1.15–1.24 (3H, m); 13C‑NMR (101 MHz, CDCl3): δ = 165.5, 162.8 (1 J CF 248 Hz), 158.6, 142.3, 135.1, 131.3 (4 J CF 3.3 Hz), 128.0 (3 J CF 8.8 Hz), 120.6, 116.3 (2 J CF 21 Hz), 55.0, 49.0, 32.8, 25.5, 24.8; 19F-NMR (377 MHz, CDCl3): δ = – 13.99; APCI-HRMS: m/z calcd. for [C19H21BrFN2O2]+ 407.0765 found 407.0767 [M+H]+. (d) A solution of 2-(3-bromo-5-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl)-N-cyclohexylacetamide (12.7 mg, 30.0 µmol) in dry DMF (0.30 mL) was treated with CuCN (8.40 mg, 90.0 µmol) at room temperature. The mixture was deareated by N2 sparging for five minutes at room temperature and heated at 120 °C for 20 hours. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography over silica gel with eluent 100% CH2Cl2 to 95:5 CH2Cl2:MeOH gives 2-(3-cyano-5-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl)-N-cyclo­hexylacetamide (28) as a white solid (3.70 mg, 34%): R f 0.21 (hexanes:EtOAc, 1:1, UV); 1H-NMR (400 MHz, CDCl3): δ = 8.07 (1H, d, 4 J 2.6 Hz), 7.87 (1H, d, 4 J 2.7 Hz), 7.34–7.41 (2H, m), 7.11–7.19 (2H, m), 6.40 (1H, d, 3 J 7.9 Hz), 4.62 (2H, s), 3.67–3.77 (1H, m), 1.85–1.94 (2H, m), 1.67–1.72 (2H, m), 1.58–1.64 (1H, m), 1.28–1.40 (2H, m), 1.13–1.26 (3H, m); 13C-NMR (101 MHz, CDCl3): δ = 164.5, 163.0 (1 J CF 248 Hz), 159.2, 147.2, 141.0, 130.5 (4 J CF 3.4 Hz), 128.1 (3 J CF 8.3 Hz), 119.9, 116.6 (2 J CF 22 Hzs), 105.6, 53.7, 49.3, 32.9, 25.5, 24.8; 19F-NMR (377 MHz, CDCl3): δ = –113.03; APCI-HRMS: m/z calcd. for [C20H21FN3O2]+ 354.1612 found 354.1609 [M+H]+. Further details can be found in the Supporting Information.