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Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 May 15; Vol. 40, pp. 127906. Date of Electronic Publication: 2021 Mar 06. - Publication Year :
- 2021
-
Abstract
- Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2'-OMe and 2'-H substitutions were also advantageous. We found that the 4'-NO <subscript>2</subscript> substituent can be replaced with a 4'-CN or 4'-CF <subscript>3</subscript> substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.<br /> (Published by Elsevier Ltd.)
- Subjects :
- Animals
Antiviral Agents chemical synthesis
Antiviral Agents metabolism
Binding Sites
Chlorocebus aethiops
Drug Stability
Humans
Microbial Sensitivity Tests
Microsomes, Liver metabolism
Molecular Docking Simulation
Molecular Structure
Niclosamide metabolism
Protein Binding
Rats
Serine Endopeptidases chemistry
Serine Endopeptidases metabolism
Structure-Activity Relationship
Vero Cells
Viral Nonstructural Proteins chemistry
Viral Nonstructural Proteins metabolism
Viral Proteins chemistry
Viral Proteins metabolism
Antiviral Agents pharmacology
Niclosamide analogs & derivatives
Niclosamide pharmacology
SARS-CoV-2 drug effects
Zika Virus drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 40
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 33689873
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.127906