Antipicornavirus activity of tetrazole analogues related to disoxaril.
A series of tetrazole analogues of Win 54954, a broad-spectrum antipicornavirus compound, has been synthesized to address the acid lability of the oxazoline ring of this series of compounds. The results of X-ray crystallography studies of several members of the oxazoline series bound to human rhinovirus type 1A and 14 have been used to design compounds in the tetrazole series with a broad spectrum of activity. Compound 16b, which has a three-carbon linkage between the isoxazole and phenyl rings and a propyl chain extending from the isoxazole ring, exhibiting an MIC80 for 15 rhinovirus serotypes of 0.20 microM as compared to 0.40 microM for Win 54954. X-ray studies of 16b bound to human rhinovirus-14 show that the propyl side chain extends into a pore in the binding site with the possibility of hydrophobic interactions with a pocket formed by Leu106 and a portion of Ser107.
Diana
G D
GD
Sterling Winthrop Pharmaceutical Research Division, Collegeville, Pennsylvania 19426.
Cutcliffe
D
D
Volkots
D L
DL
Mallamo
J P
JP
Bailey
T R
TR
Vescio
N
N
Oglesby
R C
RC
Nitz
T J
TJ
Wetzel
J
J
Giranda
V
V
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010849:Picornaviridae / Q000187:drug effects*; D012229:Rhinovirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D000998:Antiviral Agents; D007555:Isoxazoles; D013777:Tetrazoles; C062554:Win 54954; C045978:disoxaril