Strategic Design and Optimization of Umifenovir Analogues: Balancing Antiviral Efficacy and hERG Toxicity against SARS-CoV-2
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 <b>10</b> and <b>14</b> (IC<sub>50</sub> = 1.5 μM), surpassing ARB (IC<sub>50</sub> = 9.0 μM). Further refinements yielded compounds <b>42</b> (IC<sub>50</sub> = 1.1 μM) and <b>56</b> (IC<sub>50</sub> = 0.24 μM), resolving hERG toxicity (>30 μM). C3 modifications led to lead compounds <b>77</b>, <b>79</b>, and <b>81</b> (IC<sub>50</sub> = 0.67-0.7 μM), achieving superior potency while eliminating hERG toxicity. Mechanism of entry inhibition and immunofluorescence confirmed compound <b>77</b> significantly reduced SARS-CoV-2 within Vero cells, supporting their preclinical potential.
Authors
- Israful Hoque (ORCID: https://orcid.org/0000-0001-8124-0070)
- Rakesh Chawla (ORCID: https://orcid.org/0000-0002-5090-6033)
- Krishan Gopal Thakur (ORCID: https://orcid.org/0000-0003-4500-2133)
- Binita Patra
- Rajesh P. Ringe (ORCID: https://orcid.org/0000-0002-6068-4163)
- Ángel Arévalo-Martı́n (ORCID: https://orcid.org/0000-0002-0549-6098)
- Sahil Kumar (ORCID: https://orcid.org/0000-0002-4868-0741)
- Uddipta Ghosh Dastidar (ORCID: https://orcid.org/0000-0001-5094-2504)
- Nittu Singh
- Dipankar Das (ORCID: https://orcid.org/0000-0001-5699-3767)
- Arindam Talukdar (ORCID: https://orcid.org/0000-0002-7831-1795)
- Nirmal K. Das (ORCID: https://orcid.org/0000-0003-0216-7202)
- Satyajeet Das (ORCID: https://orcid.org/0000-0002-5528-0615)
- Akshay Joshi (ORCID: https://orcid.org/0009-0007-4770-3925)
- Kiran Kumar Bokara
- Yogesh Sardana
Institutions
- Indian Institute of Chemical Biology (IN)
- Centre for Cellular and Molecular Biology (IN)
- Ministry of Science and Technology (IN)
- Institute of Microbial Technology (IN)
- Academy of Scientific and Innovative Research (IN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03093
- Citations
- 6
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- Council of Scientific and Industrial Research, India
- University Grants Commission