Abstract
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.