An evaluation of the antirhinoviral activity of acetylfuran replacements for 3-methylisoxazoles. Are 2-acetylfurans bioisosteres for 3-methylisoxazoles?
As a probe of the 3-methylisoxazole portion of our broad-spectrum antipicornaviral series, a panel of 2-acetylfuran analogues was prepared as replacements for the 3-methylisoxazole ring. Comparison of the two series showed remarkable similarity in potency, spectrum of activity, logP, and electrostatic parameters. X-ray studies of 21b bound to human rhinovirus-14 showed that the 2-acetyl group adopted a syn conformation and the carbonyl oxygen acts as a hydrogen bond acceptor with ASN219 in much the same way as the nitrogen of the isoxazole. The importance of the syn conformation and the hydrogen-bonding capability was confirmed by the reduced antiviral activity of the 2-methylfuran and 2-formylfuran analogues. From the results of this study, it is apparent that the syn-2-acetylfuran ring is acting as a bioisostere for the 3-methylisoxazole.
Bailey
T R
TR
Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426-0900.
Diana
G D
GD
Mallamo
J P
JP
Vescio
N
N
Draper
T L
TL
Carabateas
P M
PM
Long
M A
MA
Giranda
V L
VL
Dutko
F J
FJ
Pevear
D C
DC
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008968:Molecular Conformation; D012229:Rhinovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D005663:Furans; D007555:Isoxazoles; C039669:2-acetylfuran