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 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.