Antipicornavirus activity of tetrazole analogs 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 rhinov...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993-10, Vol.36 (22), p.3240-3250
Main Authors: Diana, Guy D, Cutcliffe, David, Volkots, Deborah L, Mallamo, John P, Bailey, Thomas R, Vescio, Niranjan, Oglesby, Richard C, Nitz, Theodore J, Wetzel, Joseph
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Binding Sites
Biological and medical sciences
Humans
Isoxazoles - chemical synthesis
Isoxazoles - chemistry
Isoxazoles - pharmacology
Medical sciences
Microbial Sensitivity Tests
Molecular Sequence Data
Pharmacology. Drug treatments
Picornaviridae - drug effects
picornavirus
Rhinovirus - drug effects
Structure-Activity Relationship
Tetrazoles - chemical synthesis
Tetrazoles - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00074a004