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Abstract <p>The synthesis and antibacterial evaluation of a new class of hydrophilic ocotillol-type triterpenoid derivatives have been conducted, with some of the compounds demonstrating potent activity (2–32 µg/mL) against a spectrum of pathogens including drug-resistant bacteria MRSA USA300. Assessing the synergistic potential, two compounds, substituted with C<sup>12</sup> aminopropionyl and aminovaleryl respectively, were identified to enhance the efficacy of kanamycin and chloramphenicol against MRSA USA300 and <i>B. subtilis</i> 168, achieving a fractional inhibitory concentration index (FICI) below 0.5. Time-kill kinetics studies confirmed that compound substituted with C<sup>12</sup> aminovaleryl, at a 2×MIC concentration, could rapidly eliminate MRSA cells. Further exploration into the mechanism of action revealed that this compound targets bacterial cell membranes, causing structural disruption, leakage of cellular contents, and ultimately, cell death. Its low toxicity to mammalian cells was evidenced by IC<sub>50</sub> values of approximately 70 µg/mL for HeLa cells and around 100 µg/mL for HEK-293 cells. Moreover, it was found to inhibit MRSA growth rapidly without promoting significant bacterial resistance. The drug-likeness properties and ADME prediction suggested that the tested compounds, with the exception of their molecular weights, conformed to Lipinski’s rule and exhibited moderate to good oral bioavailability. In vivo studies in a murine corneal infection model substantiated the robust antibacterial activity of this compound against <i>S. aureus</i> RN4220, particularly at higher doses. Lastly, a thorough analysis of the structure-activity relationships (SAR) among the synthesized compounds was conducted, providing valuable insights that could inform the development of novel therapeutic agents beyond the existing classes of antimicrobials.</p>

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Design, Synthesis, and Antibacterial Activity Evaluation of Novel C12 Amide Analogues Based on Ocotillol

  • 期刊论文

  • 发表日期：

    2025年4月25日

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  • Hefei Huang,
  • Pengju Yang,
  • Yuting Liu,
  • Zhiwen Zhou

摘要

Abstract

The synthesis and antibacterial evaluation of a new class of hydrophilic ocotillol-type triterpenoid derivatives have been conducted, with some of the compounds demonstrating potent activity (2–32 µg/mL) against a spectrum of pathogens including drug-resistant bacteria MRSA USA300. Assessing the synergistic potential, two compounds, substituted with C12 aminopropionyl and aminovaleryl respectively, were identified to enhance the efficacy of kanamycin and chloramphenicol against MRSA USA300 and B. subtilis 168, achieving a fractional inhibitory concentration index (FICI) below 0.5. Time-kill kinetics studies confirmed that compound substituted with C12 aminovaleryl, at a 2×MIC concentration, could rapidly eliminate MRSA cells. Further exploration into the mechanism of action revealed that this compound targets bacterial cell membranes, causing structural disruption, leakage of cellular contents, and ultimately, cell death. Its low toxicity to mammalian cells was evidenced by IC50 values of approximately 70 µg/mL for HeLa cells and around 100 µg/mL for HEK-293 cells. Moreover, it was found to inhibit MRSA growth rapidly without promoting significant bacterial resistance. The drug-likeness properties and ADME prediction suggested that the tested compounds, with the exception of their molecular weights, conformed to Lipinski’s rule and exhibited moderate to good oral bioavailability. In vivo studies in a murine corneal infection model substantiated the robust antibacterial activity of this compound against S. aureus RN4220, particularly at higher doses. Lastly, a thorough analysis of the structure-activity relationships (SAR) among the synthesized compounds was conducted, providing valuable insights that could inform the development of novel therapeutic agents beyond the existing classes of antimicrobials.