Construction and Evaluation of Novel Dual-function Antifungal Inhibitors and Covalent Organic Framework Carriers Based on the Infection Microenvironment.

In this study, PD-L1 and CYP51 were selected as key dual-target enzymes, which play an important role in the process of fungal proliferation and immune suppression. A series of novel bifonazole dual-target compounds were designed through the method of fragment combination. Their chemical structure was synthesized, characterized, and evaluated. Among them, the compounds (10c-1, 14a-2, 17c-2) exhibited excellent antifungal and antidrug-resistant fungal activity in vitro. In particular, the preferred compound 14a-2 with high-efficiency dual-target inhibitor ability could block the fungal proliferation and activate the organism's immune efficacy. Moreover, the corresponding covalent organic framework carrier was also successfully constructed to improve its bioavailability. This significantly accelerated the body's recovery process from fungal infection in vivo. In summary, this study expanded the scientific frontier of antifungal drugs and provided a feasible candidate pathway for clinical treatment of fungal infections.