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

Faced with increasingly serious fungal infections and
drug resistance
issues, three different series of novel dual-target (programmed death
ligand 1/14 α-demethylase) compounds were constructed through
the fragment combination pathway in the study. Their chemical structures
were synthesized, characterized, and evaluated. Among them, preferred
compounds 10c-1, 17b-1, and 18b-2 could efficiently exert their antifungal and antidrug-resistant
fungal ability through blocking ergosterol biosynthesis, inducing
the upregulation of reactive oxygen species level, and triggering
apoptosis. Especially, compound 18b-2 exhibited the synergistic
function of fungal inhibition and immune activation. Moreover, the
covalent organic framework carrier was also generated based on the
acidic microenvironment of fungal infection to improve the bioavailability
and targeting of preferred compounds; this finally accelerated the
body’s recovery rate.