Enantiomeric Effects of Homologues of Disoxaril on the Inhibitory Activity Against Human Rhinovirus-14

Guy D. Diana; Michael J. Otto; Adi M. Treasurywala; Mark A. Mckinlay; Richard C. Oglesby; Edward G. Maliski; Michael G. Rossmann; Thomas J. Smith

doi:10.1021/jm00398a009

Enantiomeric Effects of Homologues of Disoxaril on the Inhibitory Activity Against Human Rhinovirus-14

Guy D. Diana, Michael J. Otto, Adi M. Treasurywala, Mark A. Mckinlay, Richard C. Oglesby, Edward G. Maliski, Michael G. Rossmann, Thomas J. Smith

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

X-ray crystallography studies of racemic 5-[7-[4-(4,5-dihydro-4-methyl-2-oxazolyl)phenoxy]heptyl]-3-methylisoxazole (2) 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 Leu¹⁰⁶and 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-Å 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.

Original language	English (US)
Pages (from-to)	540-544
Number of pages	5
Journal	Journal of medicinal chemistry
Volume	31
Issue number	3
DOIs	https://doi.org/10.1021/jm00398a009
State	Published - Mar 1 1988
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Enantiomeric Effects of Homologues 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 (2) 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 Leu106and 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-{\AA} 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.",

author = "Diana, {Guy D.} and Otto, {Michael J.} and Treasurywala, {Adi M.} and Mckinlay, {Mark A.} and Oglesby, {Richard C.} and Maliski, {Edward G.} and Rossmann, {Michael G.} and Smith, {Thomas J.}",

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AU - Diana, Guy D.

AU - Otto, Michael J.

AU - Treasurywala, Adi M.

AU - Mckinlay, Mark A.

AU - Oglesby, Richard C.

AU - Maliski, Edward G.

AU - Rossmann, Michael G.

AU - Smith, Thomas J.

PY - 1988/3/1

Y1 - 1988/3/1

N2 - X-ray crystallography studies of racemic 5-[7-[4-(4,5-dihydro-4-methyl-2-oxazolyl)phenoxy]heptyl]-3-methylisoxazole (2) 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 Leu106and 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-Å 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.

AB - X-ray crystallography studies of racemic 5-[7-[4-(4,5-dihydro-4-methyl-2-oxazolyl)phenoxy]heptyl]-3-methylisoxazole (2) 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 Leu106and 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-Å 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.

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Enantiomeric Effects of Homologues of Disoxaril on the Inhibitory Activity Against Human Rhinovirus-14

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