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Synthesis, sciatic nerve block activity evaluation and molecular docking of fluoro-substituted lidocaine analogs as local anesthetic agents

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Abstract

Thirty fluoro-substituted lidocaine analogs (10a–e, 11a–e, 14a–e, 15a–e, 18a–e and 19a–e) were synthesized, and their sciatic nerve block activity were evaluated as local anesthesia. Most of the compounds displayed significant potency, and compound 10a in particular was much more potent than the parent lidocaine. Fifteen analogs including 10a demonstrated pKa values of 7.5–7.8 suitable for local anesthesia. Compound 10a, 14e, and lidocaine were docked into three target receptors of local anesthetics by molecular docking studies to delineate structure-activity relationships and explain the differences in activities. Hydrophobic interactions and hydrogen bonds were identified key to molecular binding, suggesting that optimization of these interactions and/or trifluoro-substitution at the benzene ring of lidocaine could enhance the properties of lidocine analogs for local anesthesia.

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Acknowledgements

This work was supported by a grant from Jiangsu Hengrui Pharmaceutical Com. Ltd and a foundation on the integration of industry, education, and research of He’nan science and technology commission (No. 152107000041). The authors are grateful to Dr J.H. Fu (Pharmaceutical School, China Pharmaceutical University) for the determination of biological activity. We thank Amy Tong from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English draft of this paper.

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Zhengzhou University, 450002, Zhengzhou, PR China

    Wen Li, Ying Yan, Yingjie Chang, Lina Ding & Hongmin Liu

  2. Jiangsu Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, China Pharmaceutical University, 210009, Nanjing, PR China

    Wen Li & Qidong You

  3. Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province & Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education & Key Laboratory of Henan Province for Drug Quality and Evaluation, 450002, Zhengzhou, PR China

    Wen Li, Lina Ding & Hongmin Liu

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  1. Wen Li
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Li, W., Yan, Y., Chang, Y. et al. Synthesis, sciatic nerve block activity evaluation and molecular docking of fluoro-substituted lidocaine analogs as local anesthetic agents. Med Chem Res 28, 1783–1795 (2019). https://doi.org/10.1007/s00044-019-02415-4

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