靶向Ras/cAMP/PKA通路的抗flc耐药白色念珠菌协同抗真菌药物

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-07-09 Epub Date: 2026-06-11 DOI:10.1021/acsmedchemlett.6c00192

Di Zhao, Wengang Wang, Zhichang Xu, Zewei Mao, Ruirui Wang, Huan Chen* and Chunyan Hu*,

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引用次数: 0

摘要

设计并合成了一系列新的瓦西辛衍生物，并对其体外抗真菌活性进行了评价。大多数化合物与氟康唑（FLC）对耐氟康唑白色念珠菌具有协同抗真菌作用。化合物3n的活性最高（MIC50 = 1.29 μM, FICI = 0.01），对16HBE细胞无明显的细胞毒性。机制研究表明，3n与FLC联合抑制生物膜形成和外排泵活性，协同靶向Ras/cAMP/PKA通路，阻断酵母向菌丝转化。这种双重机制为治疗耐flc白色念珠菌感染提供了新的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Vasicine-Based Synergistic Antifungal Agents against FLC-Resistant Candida albicans Targeting Ras/cAMP/PKA Pathway

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Vasicine-Based Synergistic Antifungal Agents against FLC-Resistant Candida albicans Targeting Ras/cAMP/PKA Pathway

A series of novel vasicine-based derivatives were designed and synthesized, and in vitro antifungal activities were evaluated. Most compounds showed synergistic antifungal effects with fluconazole (FLC) against FLC-resistant C. albicans. Compound 3n exhibited the best activity (MIC₅₀ = 1.29 μM, FICI = 0.01) with no obvious cytotoxicity to 16HBE cells. Mechanistic studies revealed that 3n combined with FLC inhibited biofilm formation and efflux pump activity, and synergistically targeted the Ras/cAMP/PKA pathway to block yeast-to-hyphae transition. This dual mechanism provides a new strategy for treating FLC-resistant C. albicans infections.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.