Identification of sulphonamide-tethered N-((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 38; no. 1; p. 2234665
• Main Authors: ElNaggar, Mai H., Elgazar, Abdullah A., Gamal, Ghada, Hamed, Shimaa M., Elsayed, Zainab M., El-Ashrey, Mohamed K., Abood, Amira, El Hassab, Mahmoud A., Soliman, Ahmed M., El-Domany, Ramadan A., Badria, Farid A., Supuran, Claudiu T., Eldehna, Wagdy M.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01-12-2023; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Cell proliferation; click chemistry; COVID-19; Enzymes; FRET assay and moleuclar docking; Global health; Humans; Isatin; Isatin derivatives; main protease; Pandemics; Pharmaceutical sciences; Pharmacy; Proteinase inhibitors; Public health; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Sulfanilamide; Sulfonamides; Sulfonamides - pharmacology; Vaccination; Viruses; click chemistry; SARS-CoV-2; FRET assay and moleuclar docking; main protease; Isatin derivatives
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2023.2234665

SARS-CoV-2 pandemic in the end of 2019 led to profound consequences on global health and economy. Till producing successful vaccination strategies, the healthcare sectors suffered from the lack of effective therapeutic agents that could control the spread of infection. Thus, academia and the pharmaceutical sector prioritise SARS-CoV-2 antiviral drug discovery. Here, we exploited previous reports highlighting the anti-SARS-CoV-2 activities of isatin-based molecules to develop novel triazolo-isatins for inhibiting main protease (Mpro) of the virus, a crucial enzyme for its replication in the host cells. Particularly, sulphonamide 6b showed promising inhibitory activity with an IC
50
= 0.249 µM. Additionally, 6b inhibited viral cell proliferation with an IC
50
of 4.33 µg/ml, and was non-toxic to VERO-E6 cells (CC50 = 564.74 µg/ml) displaying a selectivity index of 130.4. In silico analysis of 6b disclosed its ability to interact with key residues in the enzyme active site, supporting the obtained in vitro findings.