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

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

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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