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

Bioorg Chem. 2021 Nov:116:105363. doi: 10.1016/j.bioorg.2021.105363. Epub 2021 Sep 17.

Authors

Lamya H Al-Wahaibi¹, Ahmed Mostafa², Yaser A Mostafa³, Ola F Abou-Ghadir³, Ahmed H Abdelazeem⁴, Ahmed M Gouda⁵, Omnia Kutkat², Noura M Abo Shama², Mahmoud Shehata², Hesham A M Gomaa⁶, Mostafa H Abdelrahman⁷, Fatma A M Mohamed⁸, Xuyuan Gu⁹, Mohamed A Ali², Laurent Trembleau¹⁰, Bahaa G M Youssif¹¹

Affiliations

¹ Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University, Saudi Arabia. Electronic address: lhalwahaibi@pnu.edu.sa.
² Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, Egypt.
³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Sciences, College of Pharmacy, Riyadh Elm University, Riyadh 11681, Saudi Arabia.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
⁶ Pharmacology Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
⁷ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; Chemistry Department, School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB24 3UE, United Kingdom.
⁸ Clinical Laboratory Science Department, College of Applied Medical Sciences, Jouf University, Aljouf 72341, Saudi Arabia; Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
⁹ Chemistry Department, School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB24 3UE, United Kingdom.
¹⁰ Chemistry Department, School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB24 3UE, United Kingdom. Electronic address: l.trembleau@abdn.ac.uk.
¹¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: bahaa.youssif@pharm.aun.edu.eg.

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 M^pro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 M^pro 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-M^pro 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-M^pro inhibitors that are worth being further optimized and developed.

Keywords: COVID-19; Macrocycles; Main protease; Oxazole; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Coronavirus 3C Proteases / antagonists & inhibitors*
Coronavirus 3C Proteases / metabolism
Drug Discovery*
Humans
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology*
Oxazoles / chemical synthesis
Oxazoles / chemistry
Oxazoles / pharmacology*
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
SARS-CoV-2 / drug effects*
SARS-CoV-2 / enzymology

Substances

Antiviral Agents
Macrocyclic Compounds
Oxazoles
Protease Inhibitors
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases