Discovery and Optimization of Quinoline Analogues as Novel Potent Antivirals against Enterovirus D68.
J Med Chem
; 65(21): 14792-14808, 2022 11 10.
Article
in En
| MEDLINE
| ID: mdl-36254462
ABSTRACT
Enterovirus D68 (EV-D68) is a nonpolio enterovirus that is mainly transmitted through respiratory routes and poses a potential threat for large-scale spread. EV-D68 infections mostly cause moderate to severe respiratory diseases in children and potentially induce neurological diseases. However, there are no specific antiviral drugs or vaccines against EV-D68. Herein, through virtual screening and rational design, a series of novel quinoline analogues as anti-EV-D68 agents targeting VP1 were identified. Particularly, 19 exhibited potent antiviral activity with an EC50 value ranging from 0.05 to 0.10 µM against various EV-D68 strains and showed inhibition of viral replication verified by Western blot, immunofluorescence, and plaque formation assay. Mechanistic studies indicated that the anti-EV-D68 agents work mainly by interacting with VP1. The acceptable bioavailability of 23.9% in rats and significant metabolic stability in human liver microsome (Clint = 10.8 mL/min/kg, t1/2 = 148 min) indicated that compound 19 with a novel scaffold was worth further investigation.
Full text:
1
Database:
MEDLINE
Main subject:
Quinolines
/
Respiratory Tract Infections
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Enterovirus
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Enterovirus D, Human
/
Enterovirus Infections
Limits:
Animals
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Child
/
Humans
Language:
En
Year:
2022
Type:
Article