TY  - JOUR
ID  - open3223
UR  - http://crdd.osdd.net/open/3223/
IS  - 9
A1  - Hoque, Israful
A1  - Singh, Nittu
A1  - Ghosh Dastidar, Uddipta
A1  - Martin, Alna Kuriyickal
A1  - Joshi, Akshay
A1  - Sardana, Yogesh
A1  - Singh Chawla, Ravneet
A1  - Das, Nirmal
A1  - Patra, Binita
A1  - Devi, Renuga
A1  - Das, Satyajeet
A1  - Das, Dipankar
A1  - Kumar, Sahil
A1  - Ringe, Rajesh P
A1  - Bokara, Kiran Kumar
A1  - Thakur, Krishan Gopal
A1  - Talukdar, Arindam
Y1  - 2025/05//
N2  - 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 ?M), surpassing ARB (IC50 = 9.0 ?M). Further refinements yielded compounds 42 (IC50 = 1.1 ?M) and 56 (IC50 = 0.24 ?M), resolving hERG toxicity (>30 ?M). C3 modifications led to lead compounds 77, 79, and 81 (IC50 = 0.67-0.7 ?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.
PB  - American Chemical Society (ACS)
JF  - J. Med. Chem.
VL  - 68
TI  - Strategic design and optimization of Umifenovir analogues: Balancing antiviral efficacy and hERG toxicity against SARS-CoV-2
SP  - 9371
EP  - 9406
ER  -