Vanillic acid (VA) — a naturally occurring phenolic compound in plants — is not only used as a flavoring agent but also a prominent metabolite post tea consumption. VA and its associated compounds are believed to play a significant role in preventing diseases, underscoring the need for a systematic investigation. Herein, we report a 4-step synthesis employing the classical organic reactions, such as Willamson’s alkylation, Fischer-Spier reaction, and Steglich esterification, complemented with a protection-deprotection strategy to prepare 46 VA derivatives across the five series (–, –, , –, –, –) in high yields. The synthesized compounds were investigated for their antifungal, anti-inflammatory, and toxic effects. Notably, compound demonstrated remarkable ROS inhibition with an IC value of 5.1 ± 0.7 µg/mL, which is more than twice as effective as the standard ibuprofen drug. A subset of the synthesized derivatives (, , , –, , , and ) manifested their antifungal effect against drug-resistant strains. Compound , in particular, revealed synergism with the established antifungal drugs amphotericin B (AMB) and fluconazole (FLZ), doubling FLZ's potency against azole resistant ATCC 36082. Furthermore, improved the potency of these antifungals against FLZ-sensitive strains, including ATCC 2001 and ATCC 22019, as well as various multidrug-resistant (MDR) strains, namely ATCC 14053, CL1, and SH2L OM341600. Additionally, pharmacodynamics of compound was examined using time-kill assay, and a benign safety profile was observed with no hemolytic activity in whole blood, and no cytotoxicity towards the normal BJ human cell line. The synergistic potential of was further investigated through both experimental methods and docking simulations.These findings highlight the therapeutic potential of VA derivatives, particularly in addressing inflammation and circumventing FLZ resistance in .

中文翻译：

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释放香草酸的潜力：对抗炎症和规避唑类抗性真菌感染的自然配方的新变化

香草酸 (VA) 是植物中天然存在的酚类化合物，不仅用作调味剂，而且还是茶饮后的重要代谢物。 VA 及其相关化合物被认为在预防疾病方面发挥着重要作用，这强调了系统研究的必要性。在此，我们报告了一种采用经典有机反应（例如 Willamson 烷基化、Fischer-Spier 反应和 Steglich 酯化）的 4 步合成方法，并辅以保护-去保护策略，制备了 5 个系列的 46 种 VA 衍生物（-、-、 , –, –, –) 的高产量。研究了合成化合物的抗真菌、抗炎和毒性作用。值得注意的是，该化合物表现出显着的 ROS 抑制作用，IC 值为 5.1 ± 0.7 µg/mL，其效果是标准布洛芬药物的两倍以上。合成衍生物的一个子集（、、、、-、、、和）表现出对耐药菌株的抗真菌作用。特别是，化合物 与已建立的抗真菌药物两性霉素 B (AMB) 和氟康唑 (FLZ) 具有协同作用，使 FLZ 对唑类抗性 ATCC 36082 的效力加倍。此外，还提高了这些抗真菌药物对 FLZ 敏感菌株（包括 ATCC 2001 和 ATCC 2001）的效力。 ATCC 22019，以及各种多重耐药 (MDR) 菌株，即 ATCC 14053、CL1 和 SH2L OM341600。此外，使用时间杀灭试验检查了化合物的药效学，观察到良好的安全性，全血中没有溶血活性，并且对正常 BJ 人细胞系没有细胞毒性。通过实验方法和对接模拟进一步研究了 VA 的协同潜力。这些发现突出了 VA 衍生物的治疗潜力，特别是在解决炎症和规避 FLZ 耐药性方面。