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Research Article

QSAR analysis of [(biphenyloxy)propyl]isoxazoles: agents against coxsackievirus B3

    Eugene N Muratov

    † Author for correspondence

    Laboratory of Molecular Modeling, Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina, Beard Hall 301, CB#7563, Chapel Hill, NC 27599, USA.

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    Email the corresponding author at murik@email.unc.edu

    ,
    Ekaterina V Varlamova

    Laboratory of Theoretical Chemistry, Department of Molecular Structure, A.V. Bogatsky Physical Chemical Institute, National Academy of Sciences of Ukraine, Lustdorfskaya Doroga 86, Odessa, 65080, Ukraine

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    ,
    Anatoly G Artemenko

    Laboratory of Theoretical Chemistry, Department of Molecular Structure, A.V. Bogatsky Physical Chemical Institute, National Academy of Sciences of Ukraine, Lustdorfskaya Doroga 86, Odessa, 65080, Ukraine

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    ,
    Tat’yana Khristova

    Laboratory of Theoretical Chemistry, Department of Molecular Structure, A.V. Bogatsky Physical Chemical Institute, National Academy of Sciences of Ukraine, Lustdorfskaya Doroga 86, Odessa, 65080, Ukraine

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    ,
    Victor E Kuz’min

    Laboratory of Theoretical Chemistry, Department of Molecular Structure, A.V. Bogatsky Physical Chemical Institute, National Academy of Sciences of Ukraine, Lustdorfskaya Doroga 86, Odessa, 65080, Ukraine

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    ,
    Vadim A Makarov

    Laboratory of Biochemistry of Stresses in Microorganisms, Institute of Biochemistry RAS, Moscow, 119071, Russia

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    ,
    Olga B Riabova

    Laboratory of Biochemistry of Stresses in Microorganisms, Institute of Biochemistry RAS, Moscow, 119071, Russia

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    ,
    Peter Wutzler

    Institute of Virology & Antiviral Therapy, Jena University Hospital, Germany

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    &
    Michaela Schmidtke

    Institute of Virology & Antiviral Therapy, Jena University Hospital, Germany

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    Published Online:23 Dec 2010https://doi.org/10.4155/fmc.10.278

    Abstract

    Background: Antiviral drugs are urgently needed for the treatment of acute and chronic diseases caused by enteroviruses such as coxsackievirus B3 (CVB3). The main goal of this study is quantitative structure–activity relationship (QSAR) analysis of anti-CVB3 activity (clinical CVB3 isolate 97927 [log IC50, µM]) and investigation of the selectivity of 25 ([biphenyloxy]propyl)isoxazoles, followed by computer-aided design and virtual screening of novel active compounds. Discussion: The 2D QSAR obtained models are quite satisfactory (R2 = 0.84–0.99, Q2 = 0.76–0.92, R2ext = 0.62–0.79). Compounds with high antiviral activity and selectivity have to contain 5-trifluoromethyl-[1,2,4]oxadiazole or 2,4-difluorophenyl fragments. Insertion of 2,5-dimethylbenzene, napthyl and especially biphenyl substituents into investigated compounds substantially decreases both their antiviral activity and selectivity. Several compounds were proposed as a result of design and virtual screening. A high level of activity of 2-methoxy-1-phenyl-1H-imidazo[4,5-c]pyridine (sm428) was confirmed experimentally. Conclusion: Simplex representation of molecular structure allows successful QSAR analysis of anti-CVB3 activity of ([biphenyloxy]propyl)isoxazole derivatives. Two possible ways of battling CVB3 are considered as a future perspective.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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