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

Abstract

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 (MIC 50 , 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.

From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency In Vitro and In Vivo

“…Furthermore, transmission electron microscopy (TEM) was used to confirm the effect of compounds on fungal ultrastructers. , In the control group (Figure A,C, and E), normal C. albicans cells have regular ellipse structures with dense mannan coats in cell walls and smooth cell membranes.…”

“…Furthermore, transmission electron microscopy (TEM) was used to confirm the effect of compounds on fungal ultrastructers. 35,36 In the control group (Figure 9A,C, and E), normal C. albicans cells have regular ellipse structures with dense mannan coats in cell walls and smooth cell membranes. After treatment with 28 (Figure 9B,D,F), the mannan layer became thinner while the inner β-glucan layer was swollen, suggesting an architecture remodeling happened in fungal cell walls.…”

Design, Synthesis, and Activity Evaluation of Novel Benzazole Bifunctional Antifungal Inhibitors with an LDH Carrier

“…The preferred compounds 9a-2 , 12a-2 , and 12b-1 demonstrated the exceptional antifungal and antidrug-resistant fungal activity. In order to further investigate their dual-target inhibition potential, the corresponding assays were conducted, and the results are summarized in Table . These preferred compounds with the range of IC 50 values (0.016 ± 0.002–0.256 ± 0.029) exhibited obvious dual-target inhibition effects.…”

Construction and Activity Evaluation of Novel Bifunctional Inhibitors and a COF Carrier Based on a Fungal Infection Microenvironment

“…The antifungal activity of these synthesized compounds was assessed in vitro using the liquid medium dilution method. 35 Several representative pathogenic fungi were selected as test strains, including Candida spp. 8001), and their sources are summarized in Table S1.…”