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.

中文翻译：

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基于真菌感染微环境的新型双功能抑制剂和COF载体的构建及活性评价


面对日益严重的真菌感染和耐药问题，研究中通过片段组合途径构建了三个不同系列的新型双靶点（程序性死亡配体1/14α-去甲基酶）化合物。对它们的化学结构进行了合成、表征和评估。其中，优选的化合物10c-1、17b-1和18b-2可通过阻断麦角甾醇生物合成、诱导活性氧水平上调、引发细胞凋亡，有效发挥其抗真菌和抗耐药真菌的能力。特别是，化合物18b-2表现出真菌抑制和免疫激活的协同功能。此外，还基于真菌感染的酸性微环境生成了共价有机骨架载体，以提高优选化合物的生物利用度和靶向性；这终于加快了身体的恢复速度。