Design, synthesis, and activity evaluation of novel arylpyrrolidinones NMT antifungal inhibitors.

N-Myristoyltransferase (NMT) is essential for fungal pathogenicity by regulating the membrane localization and biological functions of key signaling proteins. Based on this target, three series of novel arylpyrrolidinone-based NMT inhibitors were designed using a scaffold-growth strategy, synthesized, and biologically evaluated. Among them, compounds 8b, 8c, and 9b showed potent NMT inhibitory activity, with IC50 values ranging from 93.20 to 152.3 nM, and exhibited broad-spectrum antifungal activity against both wild-type and multidrug-resistant fungal isolates. Mechanistic studies indicated that these compounds triggered rapid intracellular ROS accumulation, which further led to DNA damage, mitochondrial depolarization, and fungal cell death. In murine systemic infection models, these compounds demonstrated significant in vivo efficacy with low toxicity and also showed immunomodulatory potential, as evidenced by accelerated pathogen clearance and improved resolution of infection. Overall, these results suggest that arylpyrrolidinone-based NMT inhibitors are promising lead compounds for antifungal drug development.