2. Academic Validation
  3. Design, synthesis, and antiviral activity of fragmented-lapatinib aminoquinazoline analogs towards SARS-CoV-2 inhibition

Design, synthesis, and antiviral activity of fragmented-lapatinib aminoquinazoline analogs towards SARS-CoV-2 inhibition

  • Eur J Med Chem. 2025 Mar 15:286:117303. doi: 10.1016/j.ejmech.2025.117303.
Ayomide Adediji 1,  Akeanan Sroithongmoon 1,  Aphinya Suroengrit 2,  Patcharin Wilasluck 3,  Peerapon Deetanya 3,  Kamonpan Sanachai 4,  Kun Karnchanapandh 5,  Siwaporn Boonyasuppayakorn 2,  Kittikhun Wangkanont 3,  Thanyada Rungrotmongkol 6,  Tanatorn Khotavivattana 7
Affiliations

Affiliations

  • 1 Center of Excellence in Natural Products, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand.
  • 2 Center of Excellence in Applied Medical Virology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
  • 3 Center of Excellence for Molecular Biology and Genomics of Shrimp, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand; Center of Excellence for Molecular Crop, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
  • 4 Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen, 40002, Thailand.
  • 5 Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.
  • 6 Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand; Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
  • 7 Center of Excellence in Natural Products, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand. Electronic address: tanatorn.k@chula.ac.th.
PMID: 39879938 DOI: 10.1016/j.ejmech.2025.117303
Abstract

The severe impact of COVID-19 on global health and economies highlights the critical need for innovative treatments. Recently, lapatinib, a drug initially used for breast Cancer, has been identified as a potential inhibitor of the main protease (Mpro) of SARS-CoV-2, meriting further investigation. Utilizing rational design strategies and guided by MD simulations, we developed novel aminoquinazoline analogs based on fragmented lapatinib's structure. Preliminary computational screenings identified promising candidates, which were synthesized using a concise 3-4 step process. In vitro assays demonstrated notable Antiviral efficacy against SARS-CoV-2-infected cells for all analogs, with Bb1 showing an EC50 of 1.10 μM and significantly lower toxicity (13.55 % at 50 μM) compared to lapatinib. Further studies confirmed that these analogs effectively inhibit SARS-CoV-2 Mpro, with Bb7 displaying the highest activity. MD simulations revealed that Bb7 achieves stability within the Mpro binding pocket through interactions with specific residues. These findings indicate that aminoquinazoline analogs hold significant promise as therapeutic candidates for COVID-19.

Keywords

COVID-19; Inhibitor; Lapatinib; Main protease enzyme; SARS-CoV-2.

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