Targeted screening and rational optimization of bazedoxifene analogs as pan-variant SARS-CoV-2 entry inhibitors with improved pharmacokinetics

  • Eur J Med Chem. 2025 Dec 16:304:118462. doi: 10.1016/j.ejmech.2025.118462.
Binita Patra  1 ,  Nirmal Das  1 ,  Akshay Joshi  2 ,  Sahil Kumar  2 ,  Renuga Devi  3 ,  Biswajit Kundu  1 ,  Nanda Kumar Raja  4 ,  Israful Hoque  1 ,  Soupayan Pal  1 ,  Anindita Dey  1 ,  Jafar Sarif  5 ,  Nittu Singh  2 ,  Nandha Kumaar  3 ,  Ravneet Singh Chawla  2 ,  Uddipta Ghosh Dastidar  6 ,  Alna Kuriyickal Martin  3 ,  Kanagasabai Balamurugan  4 ,  Bokara Kiran Kumar  7 ,  Rajesh P Ringe  2 ,  Dipyaman Ganguly  8 ,  Krishan Gopal Thakur  9 ,  Arindam Talukdar  10
Affiliations
  • 1. Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India.
  • 2. CSIR-Institute of Microbial Technology, Ministry of Science & Technology, Sector 39A Rd, 39A, Sector 39, 160036, Chandigarh, India.
  • 3. CSIR-Center for Cellular and Molecular Biology, Medical Biotechnology Complex, Uppal Road, Hyderabad, Telangana, India.
  • 4. Advanced Materials Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai, India, 600020; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 5. IICB-Translational Research Unit of Excellence, Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, CN6, Sector V, Salt Lake, Kolkata, 700091, WB, India.
  • 6. Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 7. CSIR-Center for Cellular and Molecular Biology, Medical Biotechnology Complex, Uppal Road, Hyderabad, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 8. IICB-Translational Research Unit of Excellence, Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, CN6, Sector V, Salt Lake, Kolkata, 700091, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 9. CSIR-Institute of Microbial Technology, Ministry of Science & Technology, Sector 39A Rd, 39A, Sector 39, 160036, Chandigarh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: [email protected].
  • 10. Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: [email protected].
PMID: 41448049 DOI: 10.1016/j.ejmech.2025.118462
Abstract

Through a focused screening of FDA-approved drugs using a spike RBD-ACE2 interaction assay, we identified bazedoxifene, a selective Estrogen receptor Modulator (SERM), as an unexpected yet potent entry inhibitor of SARS-CoV-2. Bazedoxifene disrupted spike-mediated attachment and demonstrated robust inhibition in both pseudovirus (IC50 = 1.11 μM) and live-virus (IC50 = 2.1 μM) assays. Mechanistic validation through RT-qPCR, pseudovirus entry assays, and immunofluorescence imaging confirmed entry-stage action. Notably, bazedoxifene retained efficacy across key SARS-CoV-2 variants (WT, Delta, Beta, Omicron BA.1/BA.5) and the zoonotic sarbecovirus Khosta-2, underscoring its broad-spectrum potential. A systematic SAR campaign introduced modifications at N1, C3 methyl, and the phenolic hydroxyls (C4'/C5), identifying compound 74 (C5 isosteric replacement) as a superior analog. Compound 74 exhibited pseudovirus IC50 = 1.6 μM, live-virus IC50 = 0.45 μM, and showed significantly improved PK parameters: ∼6-fold lower clearance, >10-fold longer half-life, and 7-8-fold higher AUC compared to both bazedoxifene and compound 66 (C4' modification). The metabolic stabilisation achieved through C5 modification validates it as a key hotspot driving glucuronidation and rapid clearance in bazedoxifene. Altogether, the potent Antiviral activity, metabolic resilience, and enhanced drug-like properties of compound 74 position it as a promising lead for next-generation, entry-targeted Antiviral development.

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