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<p>P2 × 7R is crucial in the pathogenesis of chronic inflammatory diseases, and its activation leads to the release of pro-inflammatory cytokines, exacerbating the inflammatory response. Two new series of scarce cyclic <i>N</i>,<i> O</i>-acetals (ATF 61–74) and corresponding opened <i>N</i>,<i> N</i>-aminals (CS 1–14) have been designed as novel potential P2RX7 antagonists, then synthesized and evaluated for their anti-inflammatory properties through investigating the pro-inflammatory markers and also for their antifungal activity against <i>Candida albicans</i>. Three compounds (ATF 64, CS 8, and CS 9) exhibited dual antifungal and anti-inflammatory properties. ATF 64, CS 8, and CS 9 reduced ROS production and IL-1β expression in macrophages and intestinal cells in a manner correlated with NF-KB expression. These compounds showed excellent antifungal activity against clinical isolates of <i>C. albicans</i> resistant to fluconazole and caspofungin, and reduced <i>C. albicans</i> biofilm formation. Treatment with CS 8 or CS 9 protected the nematode <i>Caenorhabditis elegans</i> against infection with <i>C. albicans</i> and enhanced antimicrobial gene expression. This duality of action offers a promising new pharmacological strategy to counteract inflammatory diseases and propels <i>N</i>,<i> N</i>-aminals as promising candidates for future optimization and investigation.</p>

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Cyclic N, O-acetals and corresponding opened N, N-aminals as new scaffolds with promising anti-inflammatory and antifungal activities against Candida albicans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月11日

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  • Christine Safi,
  • Louis Camaioni,
  • Mohamed Othman,
  • Dylan Lambert,
  • Mathys Buisine,
  • Ata Martin Lawson,
  • Alina Ghinet,
  • Adam Daïch,
  • Samir Jawhara

摘要

P2 × 7R is crucial in the pathogenesis of chronic inflammatory diseases, and its activation leads to the release of pro-inflammatory cytokines, exacerbating the inflammatory response. Two new series of scarce cyclic N, O-acetals (ATF 61–74) and corresponding opened N, N-aminals (CS 1–14) have been designed as novel potential P2RX7 antagonists, then synthesized and evaluated for their anti-inflammatory properties through investigating the pro-inflammatory markers and also for their antifungal activity against Candida albicans. Three compounds (ATF 64, CS 8, and CS 9) exhibited dual antifungal and anti-inflammatory properties. ATF 64, CS 8, and CS 9 reduced ROS production and IL-1β expression in macrophages and intestinal cells in a manner correlated with NF-KB expression. These compounds showed excellent antifungal activity against clinical isolates of C. albicans resistant to fluconazole and caspofungin, and reduced C. albicans biofilm formation. Treatment with CS 8 or CS 9 protected the nematode Caenorhabditis elegans against infection with C. albicans and enhanced antimicrobial gene expression. This duality of action offers a promising new pharmacological strategy to counteract inflammatory diseases and propels N, N-aminals as promising candidates for future optimization and investigation.