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Synthesis, Cytotoxic, and Antibacterial Evaluation of C-12 Substituted Ocotillol-type Derivatives

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Abstract

A novel series of ocotillol-type triterpenoid derivatives have been synthesized to evaluate for their antibacterial activity, structure-activity relationships (SARs), and antibacterial mechanism. Compound (Vl), which were found to be the most active one, displayed good antibacterial activity with minimum inhibitory concentrations (MICs) of 2–8 μg/mL against Gram+ bacteria and 8–32 μg/mL against Gram– bacteria. Further testing against drug-resistant bacteria also showed that (Vk) and (Vl) exhibited potent antibacterial activity with MICs of 4–32 μg/mL against MRSA and K. pneumonia. The following synergistic antibacterial activity revealed that compound (Vl) significantly improved the susceptibility of MRSA USA300 and E.coli DH5α to kanamycin and chloramphenicol. Further research suggested that (Vl) displayed obvious bactericidal activity against MRSA at 2 MIC while it only showed bacteriostatic effects at MIC. This active molecule (Vl) also induced bacterial resistance more slowly than norfloxacin and chloramphenicol. Moreover, compound (Vl) not only had low toxicity, but also could rapidly inhibit the growth of drug-resistant bacteria by damaging cell membranes, and the incidence of drug resistance was obviously lower than that of positive control group. Additionally, the properties of absorption, distribution, metabolism, and excretion (ADME) of these compounds demonstrated their drug-likeness with moderate oral absorption and blood-brain barrier permeability. Preliminary in vivo results also confirmed that (Vl) could reduce the number of viable colonies in the infected cornea at a high concentration (3.2 mg/mL). These results suggested that ocotillol-type triterpenoid derivatives represent as potential leads for the development of antibacterial agents against antibiotic-resistant superbugs and deserve further attention.

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Funding

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, Hubei Three Gorges Polytechnic, 443002, Yichang, China

    Jiangong Liu & Huili Zhang

  2. Third-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, China

    Xiaoyu Zhang, Shuo Wang & Zhiwen Zhou

  3. Department of Pharmacy, College of Medicine and Health Sciences, China Three Gorges University, 443002, Yichang, China

    Xiaoyu Zhang, Shuo Wang & Zhiwen Zhou

Authors
  1. Jiangong Liu
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  2. Xiaoyu Zhang
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  3. Shuo Wang
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  4. Huili Zhang
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  5. Zhiwen Zhou
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Contributions

Authors HZ and ZZh designed the experiments. Authors JL and XZ synthesized the derivatives and carried out their NMR analysis. Author SW completed pharmacological analysis and data processing. Authors JL, HZ, and ZZ contributed to manuscript preparation. All authors participated in the discussions.

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Correspondence to Huili Zhang or Zhiwen Zhou.

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The data that support the findings of this study are available from the corresponding author upon reasonable request. This article does not contain any studies involving animals or human participants performed by any of the authors. Informed consent was not required for this article. No conflict of interest was declared by the authors.

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Liu, J., Zhang, X., Wang, S. et al. Synthesis, Cytotoxic, and Antibacterial Evaluation of C-12 Substituted Ocotillol-type Derivatives. Russ J Bioorg Chem 49, 1452–1466 (2023). https://doi.org/10.1134/S1068162023060249

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