Design, Synthesis, and Activity Evaluation of Novel Dual-Target Inhibitors with Antifungal and Immunoregulatory Properties

Dual-target (CYP51/PD-L1) plays an important role in the process of fungal proliferation and immune suppression. A series of novel quinazoline compounds with dual-target inhibition function was constructed using the skeleton growth method, and their structures were synthesized, characterized, and evaluated. Among them, the perfected compounds (L11, L20, L21) were selected for further study, which exhibited remarkable biological activity against different fungal strains (MIC50, 0.25-2.0 μg/mL) in vitro. On the one hand, these compounds inhibited CYP51 activity, induced ROS aggregation, and mitochondrial damage; this ultimately caused fungal lysis and death. On the other hand, they also effectively activated the body's immune ability by blocking the interaction between PD-L1 and PD-1, slowed down the inflammatory reaction, and accelerated the recovery process of fungal infections.