Structure-guided optimization of N-(5-((2-oxopropyl) thio)-1,3,4-thiadiazol-2-yl) propionamide frameworks as potent SARS-CoV-2 Mpro inhibitor for treating coronavirus disease

  • Bioorg Chem. 2026 Jun 15:180:110102. doi: 10.1016/j.bioorg.2026.110102.
Maher S Alwethaynani  1 ,  Reem Nabil Hassan  2 ,  Rafaqat Hussain  3 ,  Hina Sarfraz  4 ,  Asma Sardar  5 ,  Faisal Asif  6 ,  Yousaf Khan  7 ,  Ammena Y Binsaleh  8 ,  Nawal Al-Hoshani  9 ,  Mariam Mojally  10 ,  Hayam A Alwabsi  11 ,  Rania Ali El Hadi Mohamed  9
Affiliations
  • 1. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia.
  • 2. Department of Biological sciences, Faculty of Science, King Abdulaziz University (KAU), P.O. Box 80141, Jeddah 21589, Saudi Arabia.
  • 3. College of Biology, Hunan University Changsha Hunan-410082, China. Electronic address: [email protected].
  • 4. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. Electronic address: [email protected].
  • 5. Department of Chemistry, Fatima Jinnah Women University, Rawalpindi 46000, Pakistan.
  • 6. Department of Chemistry, Wayne State University, 48202, United States.
  • 7. Department of Chemistry, COMSATS University Islamabad, Islamabad 45550, Pakistan.
  • 8. Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
  • 9. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
  • 10. Department of Pharmaceutical Sciences, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Makkah, Saudi Arabia.
  • 11. Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia.
PMID: 42314596 DOI: 10.1016/j.bioorg.2026.110102
Abstract

The global outbreak of COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has resulted in over 774 million cases and 7 million deaths worldwide since January 2020. Although widespread vaccination has been instrumental in reducing transmission and disease severity, there is a persistent and urgent need for effective treatments. This has made the virus's main protease (Mpro), a key enzyme in its replication cycle, a leading target for drug development. In the current research work, a schematic strategy was utilized to design, synthesize and screen the biological activity of newly prepared thiadiazole derivatives (5a-f, 9a-d and 12a-j) against Mpro as SARS-CoV-2 inhibitors. The research plan was organized into three schemes, where every step advanced from the outcome of the former one to create a clear structure activity relationship (SAR) and successively optimize biological activity. Specifically compounds 12c (IC50 = 0.03077 μM), and 12a (IC50 = 0.03356 μM) exhibited excellent inhibitory potency as compared to reference drug Nirmatrelvir (IC50 = 0.05855 μM). The Molecular docking study further validated the experimental results revealing that the synthesized molecules interacted strongly with the SARS-CoV-2 Mpro active site via multiple hydrogen bonds and hydrophobic interactions with important catalytic residues, resulting in stable enzyme inhibitor complexes consistent with the in-vitro results. Nevertheless, further cell-based Antiviral studies are required to validate the ability of these compounds to suppress SARS-CoV-2 replication under physiological conditions. However, further selectivity studies against human proteases are necessary to evaluate potential off-target effects and safety profiles.

Keywords
DFT and ADME investigation; MD simulations; Molecular docking; SARS-CoV-2 M(pro); Thiadiazole.
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