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.