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

Abstract

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.

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

“…The microenvironment of fungal infection (pH values: 4.0–6.5) exhibited the acidic characteristics, stemming from inflammatory responses and the metabolites of pathogenic fungi. , The degradable covalent organic framework (COF) was constructed as the delivery carrier, which could improve the bioavailability of preferred compound 18b-2 and eliminate its adverse reactions. In the process, 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde (Tp) and terephthalo-hydrazide (Bch) were selected as starting materials; they could generate the hydrazone COF (Tp-Bch) skeleton through condensation reactions in the binary solvent system (1,4-dioxane/trimethylbenzene), and the corresponding structural characterization was verified using Fourier transform infrared (FT-IR) spectroscopy and powder X-ray diffraction (PXRD), which suggested that the COF (Tp-Bch) skeleton with the specific crystal structure has been properly constructed.…”

“…The microenvironment of fungal infection (pH values: 4.0−6.5) exhibited the acidic characteristics, stemming from inflammatory responses and the metabolites of pathogenic fungi. 24,37 The degradable covalent organic framework (COF) was constructed as the delivery carrier, which could improve the bioavailability of preferred compound 18b-2 and eliminate its adverse reactions.…”

“…When these ICIs were further combined with antifungal drugs, the rehabilitation rate of the infection region showed the acceleration trend. , However, the combination therapy also exhibited some unavoidable drawbacks, such as drug interactions, metabolic burden, and uneven absorption. , Based on the aforementioned analysis, the dual-target (CYP51/PD-L1) drug design strategy was proposed to guide the construction of novel compounds, which could simultaneously exert the biological activity of fungal inhibition and immune activation and avoid the drawbacks of combination therapy . Moreover, the corresponding carrier with targeting capability should also be generated to improve the therapeutic effect of novel compounds and eliminate the potential adverse reactions …”

“…23 Moreover, the corresponding carrier with targeting capability should also be generated to improve the therapeutic effect of novel compounds and eliminate the potential adverse reactions. 24 In the study, the novel dual-target (CYP51/PD-L1) compounds with different skeletal structures were designed, synthesized, and characterized. Their biological activity and action mechanism were evaluated to determine the preferred compounds.…”

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

“…To further validate the binding ability between the perfected compounds 9a-2, 12a-2, and 12b-1 with the PD-L1 receptor, their affinity data were obtained though surface plasmon resonance (SPR) experiments. 33 During the process, their binding statuses are continuously monitored and summarized in Figure 6. The KD values of these preferred compounds 9a-2, 12a-2, and 12b-1 were located in the range from 8.77 e −9 to 4.01 e −8 , indicating they exerted highly efficient affinity with PD-L1.…”