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Antiviral Agents

In Vitro Activities of Benzimidazole d- and l-Ribonucleosides against Herpesviruses

Stephanie L. Williams, Caroll B. Hartline, Nicole L. Kushner, Emma A. Harden, Deborah J. Bidanset, John C. Drach, Leroy B. Townsend, Mark R. Underwood, Karen K. Biron, Earl R. Kern
Stephanie L. Williams
1University of Alabama School of Medicine, Birmingham, Alabama
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Caroll B. Hartline
1University of Alabama School of Medicine, Birmingham, Alabama
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Nicole L. Kushner
1University of Alabama School of Medicine, Birmingham, Alabama
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Emma A. Harden
1University of Alabama School of Medicine, Birmingham, Alabama
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Deborah J. Bidanset
1University of Alabama School of Medicine, Birmingham, Alabama
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John C. Drach
2University of Michigan, Ann Arbor, Michigan
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Leroy B. Townsend
2University of Michigan, Ann Arbor, Michigan
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Mark R. Underwood
3GlaxoSmithKline, Inc., Research Triangle Park, North Carolina
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Karen K. Biron
3GlaxoSmithKline, Inc., Research Triangle Park, North Carolina
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Earl R. Kern
1University of Alabama School of Medicine, Birmingham, Alabama
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  • For correspondence: kern@uab.edu
DOI: 10.1128/AAC.47.7.2186-2192.2003
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    FIG. 1.

    Structures of benzimidazole ribonucleosides.

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  • TABLE 1.

    Effect of benzimidazole nucleosides on alphaherpesvirus replication

    Assay for:50% inhibitory concn (μM)a
    ACVBDCRB1263W94275175X
    Virus
        HSV-14.1 ± 0.9>251>53>50
        HSV-23.5 ± 3.1>251>53>50
        VZV0.7 ± 0.3>50>266>50
    Cytotoxicity
        Stationary cellsb>405170 ± 30243152
        Proliferating cellsc>405184 ± 2059 ± 22143 ± 28
    • ↵ a Values are expressed as mean ± standard deviation from at least two plaque reduction assays.

    • ↵ b Concentration of drug cytotoxic to 50% of HFF cells by neutral red uptake.

    • ↵ c Concentrations of drug that inhibit HFF cell growth by 50%.

  • TABLE 2.

    Activity of benzimidazole nucleosides against betaherpesviruses

    Virus (cells)Drug50% inhibitory concn (μM)
    Antiviral activityaCytotoxicity stationary cellsbToxicity proliferating cellsbSIc
    HCMVAD169 (HFF)GCV4.3 ± 0.4>361144>83
    BDCRB0.4 ± 0.3170184 ± 20425
    1263W9419.4 ± 18.624358.5 ± 22.113
    175X2.2 ± 0.5152143 ± 2869
    HHV-6AGS (HSB-2)PFA13.7 ± 8.3>166>166>12
    BDCRB>125>104>125—
    1263W94>125>133>133—
    175X>125>125>126—
    HHV-6AGS (SupT-1)CDV11.7 ± 8>15990 ± 18.1>13
    BDCRB>12569 ± 3470 ± 12—
    1263W94>133>108>105—
    175X>125>104>102—
    HHV-6BZ-29 (CBL)CDV1.6 ± 0.6>159>159>100
    BDCRB>125>109>87—
    1263W94>106>9870 ± 59—
    175X95 ± 12>122111.8 ± 14>1.3
    • ↵ a Values are the mean ± standard deviation of at least two assays. See Materials and Methods for a description of the assays.

    • ↵ b See footnote to Table 1 for description of toxicity assays.

    • ↵ c SI, selective index, cytotoxicity in stationary cells/antiviral activity. —, ≤1.

  • TABLE 3.

    Effect of benzimidazole ribonucleosides on laboratory and clinical isolates of HCMV

    Isolate50% inhibitory concn (μM)a
    BDCRB1263W94 (37°C)1263W94 (34°C)175XGCV
    AD1690.4 ± 0.219.4 ± 18.63.0 ± 32.2 ± 0.54.3 ± 0.4
    Towne1.2 ± 0.3>4414 ± 95.2 ± 2.57.2 ± 3.3
    Davis0.6 ± 0.10.6 ± 0.2NTb1.9 ± 1.14.3 ± 0.6
    Toledo1.1 ± 0.1>47 ± 72.15.3 ± 1.36.9 ± 2.3
    EC1.0 ± 0.511.2 ± 11.70.93.8 ± 0.39.7 ± 5.4
    CH0.44.01.13.04.3 ± 0.4
    C8708/17-1-10.7 ± 0.50.2 ± 0.050.32.0 ± 1.34.3 ± 0.6
    Coffman1.1 ± 0.416.5 ± 3.5113.8 ± 0.411.5 ± 5.1
    C9208/3-3-10.815.9 ± 10.611.22.0 ± 0.52.2 ± 0.8
    C9208/5-4-20.8 ± 0.31.30.72.32.4
    • ↵ a Values are expressed as the mean ± standard deviation of at least two plaque reduction assays.

    • ↵ b NT, not tested.

  • TABLE 4.

    Activity of benzimidazole ribonucleosides on drug-resistant isolates of HCMV

    Isolate50% inhibitory concn (μM)a
    BDCRB1263W94 (37°C)1263W94 (34°C)175XGCV/PFA
    C8805/37-1-11.4 ± 1.4>27152.8 ± 0.8100 ± 56
    759rD1000.4 ± 0.23.3 ± 0.62.12.1 ± 0.1113 ± 62
    GDGrP532.1 ± 1.037 ± 28.52.9 ± 0.562.8 ± 27
    C8706/13-1-11.3 ± 1.10.3 ± 0.20.82.1 ± 0.422 ± 10
    C9209/1-4-41.5 ± 1.01.0 ± 00.13.5 ± 098 ± 34
    C8914-63.3 ± 0.424 ± 240.610 ± 2.8104 ± 77
    VR4760R1.7 ± 1.50.5 ± 0.3<0.082.5 ± 1.5830 ± 28b
    VR4955R2.8 ± 0.30.7 ± 0.030.23.5 ± 0700 ± 183b
    1117R2.8 ± 050 ± 50.43.5 ± 1.042 ± 2.2
    RCMP971.085NTc2.335
    • ↵ a Values are expressed as the mean ± standard deviation of at least two plaque reduction assays.

    • ↵ b Control drug for these strains is PFA.

    • ↵ c NT, not tested.

  • TABLE 5.

    Effect of benzimidazole nucleosides against various animal CMV strains

    VirusDrug50% inhibitory concn (μM)a
    Antiviral activityCytotoxicitySIb
    MCMVGCV2.9 ± 1.4>36>12
    BDCRB371514
    1263W94>1150 ± 4<4.5
    175X20 ± 6.5158 ± 7.37.9
    RCMVGCV31 ± 1.4>361>12
    BDCRB26 ± 4.5190 ± 6.57.3
    1263W94>1131.6 ± 1.3<3.0
    175X28.2 ± 3.8117 ± 124.2
    GPCMVCDV1.6 ± 1.0>317>198
    GCV191 ± 15>361>1.9
    BDCRB2.0 ± 7188 ± 2894
    1263W94>5360 ± 9.0<1.1
    175X27 ± 8130 ± 44.8
    RhCMVGCV22 ± 8>72>3.3
    BDCRB0.4>250>625
    1263W9448 ± 4.5227 ± 3.74.7
    175X6.3 ± 0.8179 ± 1428
    • ↵ a Values are expressed as the mean ± standard deviation of at least two plaque reduction assays.

    • ↵ b SI, selective index, cytotoxicity in stationary HFF cells/antiviral activity.

  • TABLE 6.

    Effect of benzimidazole nucleosides against the gammaherpesviruses

    VirusDrug50% inhibitory concn (μM)a
    IFA-FACSbDNAELISACytotoxicitySIc
    EBVACV17.4 ± 3.63.6 ± 1.29.3 ± 0.4>187>11
    BDCRB>125>80>74>125—
    1263W9410 ± 85.1 ± 4.84.3 ± 0.8>77>7.7
    175X18 ± 310 ± 6.8>72>94>5.2
    HHV-8CDV10.2 ± 2.5NTdNT>159>16
    BDCRB>125NT NT>125—
    1263W94>133NT NT>80—
    175X>126NT NT>126—
    • ↵ a Values are expressed the mean ± standard deviation of at least two assays.

    • ↵ b IFA was performed in EBV assays and FACS was performed in HHV-8 assays.

    • ↵ c SI, selective index, cytotoxicity in Daudi or BCBL-1 cells/antiviral activity determined by IFA-FACS.

    • ↵ d NT, not tested. —, ≤1.

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In Vitro Activities of Benzimidazole d- and l-Ribonucleosides against Herpesviruses
Stephanie L. Williams, Caroll B. Hartline, Nicole L. Kushner, Emma A. Harden, Deborah J. Bidanset, John C. Drach, Leroy B. Townsend, Mark R. Underwood, Karen K. Biron, Earl R. Kern
Antimicrobial Agents and Chemotherapy Jul 2003, 47 (7) 2186-2192; DOI: 10.1128/AAC.47.7.2186-2192.2003

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In Vitro Activities of Benzimidazole d- and l-Ribonucleosides against Herpesviruses
Stephanie L. Williams, Caroll B. Hartline, Nicole L. Kushner, Emma A. Harden, Deborah J. Bidanset, John C. Drach, Leroy B. Townsend, Mark R. Underwood, Karen K. Biron, Earl R. Kern
Antimicrobial Agents and Chemotherapy Jul 2003, 47 (7) 2186-2192; DOI: 10.1128/AAC.47.7.2186-2192.2003
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KEYWORDS

antiviral agents
Benzimidazoles
Herpesvirus 1, Human
Herpesvirus 2, Human
Ribonucleosides

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