Enantiomeric effects of homologs of disoxaril on the inhibitory activity against human rhinovirus-14

Abstract

X-ray crystallography studies of racemic 5-[7-[4-(4,5-dihydro-4-methyl-2-oxazolyl)phenoxy]heptyl]- 3-methylisoxazole bound to human rhinovirus-14 (HRV-14) indicate selective binding of the S isomer. This result correlates well with the 10-fold greater activity of the S isomer as compared to the R isomer. The enantiomeric effect on activity is explained by a hydrophobic interaction of the methyl group in the case of 2a, with a pocket formed by Leu106 and Ser107. The 4-ethyl, 4-propyl, and 4-butyloxazolinyl homologues were prepared and tested against HRV-14. All of these compounds exhibited a comparable stereochemical effect. In each case, the S isomer displayed greater levels of activity than the R. The results of energetic considerations of the oxazoline ring in an 8-A pocket bound to the HRV-14 binding site suggest that the twist angle between the oxazoline and phenyl rings resulting from hydrophobic interactions of the alkyl substituents could be one of the determining factors for biological activity.

Binding affinities of structurally related human rhinovirus capsid-binding compounds are related to their activities against human rhinovirus type 14

“…A canyon or depression (about 2.5-nm deep) encircles each of the virion's pentamer vertices (22). A number of structurally related antipicornaviral compounds, which were synthesized at the Sterling Research Group, Rensselaer, N.Y. (7,8), have been instrumental as an aid in exploring the structure of rhinoviruses relative to the early events in the viral replication processes. One of these compounds, disoxaril, was reported to interact directly with the virion capsid and stabilize the capsid conformation against thermal inactivation (10).…”

Methyl-2-Thienylketopolymethyleneoxyphenyl Derivatives of Alkyl-Substituted 4,5-Dihydro-Oxazoles with Anti-Human Picornavirus Activity

“…As with homologues of disoxaril (Diana et al, 1987(Diana et al, , 1988, the introduction of alkyl groups at position 4 of the oxazoline ring improves both the anti-HRV-14 and anti-HRV-2 activity of derivatives 5 (which have six methylene groups in the ketomethylene chain connecting the thiophene ring to the 4-(oxazolin-2-yl)phenoxy moiety) while not influencing the activity of counterparts with four methylene groups (compound 4). As for WIN derivatives, S enantiomers are more active than R enantiomers.…”

“…1), it has been shown that the introduction of alkyl substituents at position 4 of the oxazoline ring led to derivatives (2) which showed greater activity than 1 against several rhinovirus serotypes (Diana et al, 1988). Among the 4-alkyloxazolines, the S enantiomer of 2a has been shown to be 10 times more effective than disoxaril in inhibiting human rhinovirus-14 .…”

The human rhinovirus: human‐pathological impact, mechanisms of antirhinoviral agents, and strategies for their discovery

“…The plaque reduction assay has been traditionally performed and accepted as the ''gold standard'' in antiviral testing. [137][138][139] However, this test is laborious, time consuming, and the evaluation is subjective. Therefore, it is not suited for the routine antiviral testing.…”