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Synthesis and Biological Evaluation of N-Substituted Sophocarpinic Acid Derivatives as Coxsackievirus B3 Inhibitors

Authors

  • Li-Mei Gao,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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    • These authors contributed equally to this work.

  • Dr. Sheng Tang,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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    • These authors contributed equally to this work.

  • Dr. Yan-Xiang Wang,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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  • Dr. Rong-Mei Gao,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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  • Dr. Xin Zhang,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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  • Dr. Zong-Gen Peng,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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  • Jian-Rui Li,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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  • Prof. Jian-Dong Jiang,

    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
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  • Prof. Yu-Huan Li,

    Corresponding author
    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
    • Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)

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  • Prof. Dan-Qing Song

    Corresponding author
    1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)
    • Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050 (PR China)

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Abstract

A series of novel N-substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti-enteroviral activities against coxsackievirus type B3 (CVB3) and coxsackievirus type B6 (CVB6) in Vero cells. Structure–activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12-nitrogen atom in (E)-β,γ-sophocarpinic acid might significantly enhance anti-CVB3 activity. Among the derivatives, (E)-12-N-(m-cyanobenzenesulfonyl)-β,γ-sophocarpinic acid (11 m), possessing a meta-cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11 m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 μM h−1 in rats, and good safety through the oral route in mice, with an LD50 value of >1000 mg kg−1; these values suggest a druggable characteristic. Therefore, compound 11 m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)-β,γ-N-(benzenesulfonyl)sophocarpinic acids to be a novel class of anti-CVB3 agents.

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