Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease

Mohamed Elagawany; Ayman Abo Elmaaty; Ahmed Mostafa; Noura M Abo Shama; Eman Y Santali; Bahaa Elgendy; Ahmed A Al-Karmalawy

doi:10.1080/14756366.2022.2105322

Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2112-2132. doi: 10.1080/14756366.2022.2105322.

Authors

Mohamed Elagawany¹, Ayman Abo Elmaaty², Ahmed Mostafa^{3

4}, Noura M Abo Shama³, Eman Y Santali⁵, Bahaa Elgendy^{6

7}, Ahmed A Al-Karmalawy⁸

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
³ Center of Scientific Excellence for Influenza Viruses, National Research Centre, Cairo, Egypt.
⁴ Institute of Medical Microbiology, German Center for Infection Research (DZIF), Justus-Liebig University Giessen, Giessen, Germany.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia.
⁶ Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences, St. Louis, MO, USA.
⁷ Chemistry Department, Faculty of Science, Benha University, Benha, Egypt.
⁸ Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.

Abstract

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of N-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound 3b achieved the most promising anti-SARS-CoV-2 activity with an IC₅₀ value of 174.7 µg/mL. On the other hand, compounds 3a, 3b, and 3c showed very promising SARS-CoV-2 Mpro inhibitory effects with IC₅₀ values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound 3b docking score was very promising (-6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound 3b showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly.

Keywords: N-(5-nitrothiazol-2-yl)-carboxamido derivatives; SAR; anti-SARS-CoV-2 Mpro; in silico; in vitro.

MeSH terms

COVID-19 Drug Treatment*
Coronavirus 3C Proteases
Cysteine Endopeptidases / metabolism
Humans
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Pandemics*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
SARS-CoV-2
Viral Nonstructural Proteins

Substances

Ligands
Protease Inhibitors
Viral Nonstructural Proteins
3C-like proteinase, SARS-CoV-2
Cysteine Endopeptidases
Coronavirus 3C Proteases

Grants and funding

The authors would like to extend their sincere appreciation to Taif University Research Supporting project number (TURSP-2020/330). Mohamed Elagawany would like to thank the Science and Technology Development Fund (Egypt) for financial support (STDF-TDG Grant 43324).