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Novel ocotillol-derived lactone derivatives: design, synthesis, bioactive evaluation, SARs and preliminary antibacterial mechanism

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Abstract

A new series of ocotillol-derived lactone derivatives were designed and synthesized to consider their antibacterial activity, structure–activity relationships (SARs), antibacterial mechanism and in vivo antibacterial efficacy. Compound 6d, which exhibited broad antibacterial spectrum, was found to be the most active with minimum inhibitory concentrations (MICs) of 1–2 μg/mL against Gram-positive bacteria and 8–16 μg/mL against Gram-negative bacteria. The subsequent synergistic antibacterial tests displayed that 6d had the ability to improve the susceptibility of MRSA USA300, B. subtilis 168, and E. coli DH5α to kanamycin and chloramphenicol. This active molecule 6d also induced bacterial resistance more slowly than norfloxacin and kanamycin. Furthermore, compound 6d was membrane active and low toxic against mammalian cells, and it could rapidly inhibit the growth of MRSA and E. coli and did not obviously trigger bacterial resistance. Compound 6d also displayed strong in vivo antibacterial activity against S. aureus RN4220 in murine corneal infection models. Additionally, absorption, distribution, metabolism, and excretion properties of this type of compounds have shown drug-likeness with good oral absorption and moderate blood–brain barrier permeability. The obtained results demonstrated that ocotillol-derived compounds are a promising class of antibacterial agents worthy of further study.

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Acknowledgements

This work was supported by Health commission of Hubei Province scientific research project (grant number WJ2019H534) and Medical and health research project of Yichang (A20-2-056).

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Authors and Affiliations

  1. Department of Pharmacy, Medical College, China Three Gorges University, Yichang, China

    Ziyi Zhang, Xianming Zeng, Shengyu Zhang & Zhiwen Zhou

  2. Department of Quality Control, China Resources Sanjiu (Huangshi) Medical & Pharmaceutical Co., Ltd, Huangshi, China

    Yunyun Zhou

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Zhang, Z., Zeng, X., Zhang, S. et al. Novel ocotillol-derived lactone derivatives: design, synthesis, bioactive evaluation, SARs and preliminary antibacterial mechanism. Mol Divers 26, 2103–2120 (2022). https://doi.org/10.1007/s11030-021-10318-z

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