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primary topic: 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
type: AcademicArticle
type: Article
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.
date: 2025-05
volume: 68
issue: 9
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

American Chemical Society (ACS)
type: Organization

J. Med. Chem.
type: Collection

Rajesh P Ringe
type: Person
given name: Rajesh P
family name: Ringe

Akshay Joshi
type: Person
given name: Akshay
family name: Joshi

Nirmal Das
type: Person
given name: Nirmal
family name: Das

Dipankar Das
type: Person
given name: Dipankar
family name: Das

Israful Hoque
type: Person
given name: Israful
family name: Hoque

Alna Kuriyickal Martin
type: Person
given name: Alna Kuriyickal
family name: Martin

Ravneet Singh Chawla
type: Person
given name: Ravneet
family name: Singh Chawla

Yogesh Sardana
type: Person
given name: Yogesh
family name: Sardana

Uddipta Ghosh Dastidar
type: Person
given name: Uddipta
family name: Ghosh Dastidar

Sahil Kumar
type: Person
given name: Sahil
family name: Kumar

Renuga Devi
type: Person
given name: Renuga
family name: Devi

Nittu Singh
type: Person
given name: Nittu
family name: Singh

Kiran Kumar Bokara
type: Person
given name: Kiran Kumar
family name: Bokara

Binita Patra
type: Person
given name: Binita
family name: Patra

Satyajeet Das
type: Person
given name: Satyajeet
family name: Das

Krishan Gopal Thakur
type: Person
given name: Krishan Gopal
family name: Thakur

Arindam Talukdar
type: Person
given name: Arindam
family name: Talukdar

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primary topic: Strategic design and optimization of Umifenovir analogues: Balancing antiviral efficacy and hERG toxicity against SARS-CoV-2