2. Academic Validation
  3. Strategic Design and Optimization of Umifenovir Analogues: Balancing Antiviral Efficacy and hERG Toxicity against SARS-CoV-2

Strategic Design and Optimization of Umifenovir Analogues: Balancing Antiviral Efficacy and hERG Toxicity against SARS-CoV-2

  • J Med Chem. 2025 May 8;68(9):9371-9406. doi: 10.1021/acs.jmedchem.4c03093.
Israful Hoque 1,  Nittu Singh 2,  Uddipta Ghosh Dastidar 1 3,  Alna Kuriyickal Martin 4,  Akshay Joshi 2,  Yogesh Sardana 4,  Ravneet Singh Chawla 2,  Nirmal Das 1,  Binita Patra 1,  Renuga Devi 4,  Satyajeet Das 2,  Dipankar Das 1,  Sahil Kumar 2,  Rajesh P Ringe 2,  Kiran Kumar Bokara 4 3,  Krishan Gopal Thakur 2 3,  Arindam Talukdar 1 3
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 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 4 CSIR-Center for Cellular and Molecular Biology, Medical Biotechnology Complex, Uppal Road, Hyderabad 500007, Telangana, India.
PMID: 40263709 DOI: 10.1021/acs.jmedchem.4c03093
Abstract

Arbidol (ARB, Umifenovir), a broad-spectrum Antiviral from Russia, lacks Food and Drug Administration (FDA) approval due to insufficient clinical data and undocumented toxicity concerns. Its indole scaffold, with six unique substitutions, enables optimization for improved efficacy. This study optimized ARB's Antiviral potency and safety by modifying the N1, C2, C3, and C4 positions. Antiviral efficacy was evaluated in SARS-CoV-2-infected VERO E6 cells, while optimization was guided by absorption, distribution, metabolism, and excretion (ADME), in vivo pharmacokinetic (PK) and hERG. Early modifications at N1 and C2 produced compounds 10 and 14 (IC50 = 1.5 μM), surpassing ARB (IC50 = 9.0 μM). Further refinements yielded compounds 42 (IC50 = 1.1 μM) and 56 (IC50 = 0.24 μM), resolving hERG toxicity (>30 μM). C3 modifications led to lead compounds 77, 79, and 81 (IC50 = 0.67-0.7 μM), achieving superior potency while eliminating hERG toxicity. Mechanism of entry inhibition and immunofluorescence confirmed compound 77 significantly reduced SARS-CoV-2 within Vero cells, supporting their preclinical potential.

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