title: Strategic design and optimization of Umifenovir analogues: Balancing antiviral efficacy and hERG toxicity against SARS-CoV-2
creator: Hoque, Israful
creator: Singh, Nittu
creator: Ghosh Dastidar, Uddipta
creator: Martin, Alna Kuriyickal
creator: Joshi, Akshay
creator: Sardana, Yogesh
creator: Singh Chawla, Ravneet
creator: Das, Nirmal
creator: Patra, Binita
creator: Devi, Renuga
creator: Das, Satyajeet
creator: Das, Dipankar
creator: Kumar, Sahil
creator: Ringe, Rajesh P
creator: Bokara, Kiran Kumar
creator: Thakur, Krishan Gopal
creator: Talukdar, Arindam
description: 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.
publisher: American Chemical Society (ACS)
date: 2025-05
type: Article
type: NonPeerReviewed
identifier:   Hoque, Israful and Singh, Nittu and Ghosh Dastidar, Uddipta and Martin, Alna Kuriyickal and Joshi, Akshay and Sardana, Yogesh and Singh Chawla, Ravneet and Das, Nirmal and Patra, Binita and Devi, Renuga and Das, Satyajeet and Das, Dipankar and Kumar, Sahil and Ringe, Rajesh P and Bokara, Kiran Kumar and Thakur, Krishan Gopal and Talukdar, Arindam  (2025) Strategic design and optimization of Umifenovir analogues: Balancing antiviral efficacy and hERG toxicity against SARS-CoV-2.  J. Med. Chem., 68 (9).  pp. 9371-9406.      
relation: http://crdd.osdd.net/open/3223/