@article{open3223,
          volume = {68},
          number = {9},
           month = {May},
          author = {Israful Hoque and Nittu Singh and Uddipta Ghosh Dastidar and Alna Kuriyickal Martin and Akshay Joshi and Yogesh Sardana and Ravneet Singh Chawla and Nirmal Das and Binita Patra and Renuga Devi and Satyajeet Das and Dipankar Das and Sahil Kumar and Rajesh P Ringe and Kiran Kumar Bokara and Krishan Gopal Thakur and Arindam Talukdar},
           title = {Strategic design and optimization of Umifenovir analogues: Balancing antiviral efficacy and hERG toxicity against SARS-CoV-2},
       publisher = {American Chemical Society (ACS)},
            year = {2025},
         journal = {J. Med. Chem.},
           pages = {9371--9406},
             url = {http://crdd.osdd.net/open/3223/},
        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 {\ensuremath{\mu}}M), surpassing ARB (IC50 = 9.0 {\ensuremath{\mu}}M). Further refinements yielded compounds 42 (IC50 = 1.1 {\ensuremath{\mu}}M) and 56 (IC50 = 0.24 {\ensuremath{\mu}}M), resolving hERG toxicity ({\ensuremath{>}}30 {\ensuremath{\mu}}M). C3 modifications led to lead compounds 77, 79, and 81 (IC50 = 0.67-0.7 {\ensuremath{\mu}}M), 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.}
}