Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

Lamya H. Al-Wahaibi; Ahmed Mostafa; Yaser A. Mostafa; Ola F. Abou-Ghadir; Ahmed H. Abdelazeem; Ahmed M. Gouda; Omnia Kutkat; Noura M. Abo Shama; Mahmoud Shehata; Hesham A.M. Gomaa; Mostafa H. Abdelrahman; Fatma A.M. Mohamed; Xuyuan Gu; Mohamed A. Ali; Laurent Trembleau; Bahaa G.M. Youssif

doi:10.1016/j.bioorg.2021.105363

Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

Lamya H. Al-Wahaibi^* (Corresponding Author), Ahmed Mostafa, Yaser A. Mostafa, Ola F. Abou-Ghadir, Ahmed H. Abdelazeem, Ahmed M. Gouda, Omnia Kutkat, Noura M. Abo Shama, Mahmoud Shehata, Hesham A.M. Gomaa, Mostafa H. Abdelrahman, Fatma A.M. Mohamed, Xuyuan Gu, Mohamed A. Ali, Laurent Trembleau^* (Corresponding Author), Bahaa G.M. Youssif^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 μM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 μM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

Original language	English
Article number	105363
Number of pages	14
Journal	Bioorganic Chemistry
Volume	116
Early online date	17 Sept 2021
DOIs	https://doi.org/10.1016/j.bioorg.2021.105363
Publication status	Published - 30 Nov 2021

Keywords

COVID-19
Oxazole
Macrocycles
SARS-CoV-2
Main protease

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Al-Wahaibi, L. H., Mostafa, A., Mostafa, Y. A., Abou-Ghadir, O. F., Abdelazeem, A. H., Gouda, A. M., Kutkat, O., Abo Shama, N. M., Shehata, M., Gomaa, H. A. M., Abdelrahman, M. H., Mohamed, F. A. M., Gu, X., Ali, M. A., Trembleau, L., & Youssif, B. G. M. (2021). Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease. Bioorganic Chemistry, 116, Article 105363. https://doi.org/10.1016/j.bioorg.2021.105363

Al-Wahaibi, LH, Mostafa, A, Mostafa, YA, Abou-Ghadir, OF, Abdelazeem, AH, Gouda, AM, Kutkat, O, Abo Shama, NM, Shehata, M, Gomaa, HAM, Abdelrahman, MH, Mohamed, FAM, Gu, X, Ali, MA, Trembleau, L & Youssif, BGM 2021, 'Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease', Bioorganic Chemistry, vol. 116, 105363. https://doi.org/10.1016/j.bioorg.2021.105363

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title = "Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease",

abstract = "We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 μM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 μM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.",

keywords = "COVID-19, Oxazole, Macrocycles, SARS-CoV-2, Main protease",

author = "Al-Wahaibi, {Lamya H.} and Ahmed Mostafa and Mostafa, {Yaser A.} and Abou-Ghadir, {Ola F.} and Abdelazeem, {Ahmed H.} and Gouda, {Ahmed M.} and Omnia Kutkat and {Abo Shama}, {Noura M.} and Mahmoud Shehata and Gomaa, {Hesham A.M.} and Abdelrahman, {Mostafa H.} and Mohamed, {Fatma A.M.} and Xuyuan Gu and Ali, {Mohamed A.} and Laurent Trembleau and Youssif, {Bahaa G.M.}",

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doi = "10.1016/j.bioorg.2021.105363",

language = "English",

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journal = "Bioorganic Chemistry",

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T1 - Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

AU - Al-Wahaibi, Lamya H.

AU - Mostafa, Ahmed

AU - Mostafa, Yaser A.

AU - Abou-Ghadir, Ola F.

AU - Abdelazeem, Ahmed H.

AU - Gouda, Ahmed M.

AU - Kutkat, Omnia

AU - Abo Shama, Noura M.

AU - Shehata, Mahmoud

AU - Gomaa, Hesham A.M.

AU - Abdelrahman, Mostafa H.

AU - Mohamed, Fatma A.M.

AU - Gu, Xuyuan

AU - Ali, Mohamed A.

AU - Trembleau, Laurent

AU - Youssif, Bahaa G.M.

PY - 2021/11/30

Y1 - 2021/11/30

N2 - We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 μM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 μM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

AB - We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 μM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 μM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

KW - COVID-19

KW - Oxazole

KW - Macrocycles

KW - SARS-CoV-2

KW - Main protease

U2 - 10.1016/j.bioorg.2021.105363

DO - 10.1016/j.bioorg.2021.105363

M3 - Article

SN - 0045-2068

VL - 116

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 105363

ER -

Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

Abstract

Keywords

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