Design, Synthesis, and Anti‐Infective Effect Against Candida Albicans of a New Urolithin Derivative

ABSTRACT Deep mucosal and organ infections caused by the infestation of Candida albicans in immunocompromised patients represent a significant cause of mortality in hospitalized patients. The rise in fungal resistance is a consequence of the overuse of antibiotics. Therefore, innovative immunostimulants must be developed to combat pathogenic fungal infections. We used urolithin A (UA), an intestinal metabolite rich in the naturally occurring polyphenolic antioxidants ellagic acid (EA) or ellagitannin (ET), as a lead compound for structural modification. Through liquid screening of 17 synthesized compounds, we discovered compound 1e effectively inhibited C. albicans biofilm formation, thereby reducing its virulence. Furthermore, it protects animals from severe infections by enhancing tolerance to infection by intestinal pathogens and reducing oxidative stress. Moreover, our findings indicate that compound 1e exerts its effects through the p38 mitogen‐activated protein kinase (MAPK) innate immune pathway, which is evolutionarily conserved. These observations not only enhance our comprehension of immune mechanisms but also provide a crucial foundation for the development of immune activators with the potential to resist pathogenic bacterial infections.