Discovery and SAR study of piperidine-based derivatives as novel influenza virus inhibitors.
Org Biomol Chem
; 12(40): 8048-60, 2014 Oct 28.
Article
in En
| MEDLINE
| ID: mdl-25184371
ABSTRACT
A series of piperidine-based derivatives were identified as novel and potent inhibitors of the influenza virus through structural modification of a compound that was selected from a high-throughput screen. Various analogues were synthesized and confirmed as inhibitors. The structureactivity relationship (SAR) studies suggested that the ether linkage between the quinoline and piperidine is critical for the inhibitory activity. The optimized compound tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate 11e had an excellent inhibitory activity against influenza virus infection from a variety of influenza virus strains, with EC50 values as low as 0.05 µM. The selectivity index value (SI = MLD50/EC50) of 11e is over 160000 based on cytotoxicity, measured by MTT assays of three cell lines. We carried out a time-of-addition experiment to delineate the mechanism of inhibition. The result indicates that 11e interferes with the early to middle stage of influenza virus replication.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Orthomyxoviridae
/
Piperidines
/
Drug Discovery
Limits:
Animals
/
Humans
Language:
En
Journal:
Org Biomol Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2014
Type:
Article