Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational libr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (13), p.3841-3847
Main Authors: Décor, Anne, Grand-Maître, Chantal, Hucke, Oliver, O’Meara, Jeff, Kuhn, Cyrille, -Forget, Léa Constantineau, Brochu, Christian, Malenfant, Eric, Bertrand-Laperle, Mégan, Bordeleau, Josée, Ghiro, Elise, Pesant, Marc, Fazal, Gulrez, Gorys, Vida, Little, Michael, Boucher, Colette, Bordeleau, Sylvain, Turcotte, Pascal, Guo, Tim, Garneau, Michel, Spickler, Catherine, Gauthier, Annick
Format: Article
Language:English
Subjects:
1-phosphatidylinositol 4-kinase
Aminothiazoles
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Design of experiment
DOE
Dose-Response Relationship, Drug
Drug Design
genotype
HRV
Human rhinovirus
Humans
Library design
mechanism of action
mice
Microbial Sensitivity Tests
Molecular Structure
molecular weight
PI4KIIIß
Rhinovirus - drug effects
Structure-Activity Relationship
structure-activity relationships
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary:We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.04.077