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Abstract：
Azoles are the main antifungal agents employed in clinical practice to treat invasive candidiasis. Nonetheless, their efficacy is limited by fungal resistance mechanisms, mainly the overexpression of efflux pumps. Consequently, candidiasis has a worrisome death rate of 75%. One potential strategy to overcome efflux-mediated resistance is to inhibit this process. Ailanthus altissima is a Chinese tree that produces several active substances, including altissimacoumarin D. Due to the low yield of its extraction and the need to search for new drugs to treat candidiasis, this study aimed to synthesize altissimacoumarin D and its analogues, as well as evaluating their ability to reverse the resistance phenotype of Candida albicans. Coumarin isofraxidin was prepared via total synthesis through a solvent-free Knoevenagel condensation as the key step. Isofraxidin and other commercially available coumarins were alkylated with prenyl or geranyl groups to yield the natural product altissimacoumarin D and seven analogues. The antifungal activity of the coumarins and their ability to reverse the fungal resistance phenotype were assessed using microbroth methodologies. Toxicity was evaluated using erythrocytes and an in silico prediction. All compounds improved the antifungal activity of fluconazole by inhibiting efflux pumps, and ACS47 and ACS50 were the most active. None of the coumarins were toxic to erythrocytes. In silico predictions indicate that ACS47 and ACS50 may be safe for human use. ACS47 and ACS50 are promising candidates when used as adjuvants in the antifungal therapy against C. albicans-resistant strains.
摘要：
唑类是临床实践中用于治疗侵袭性念珠菌病的主要抗真菌药。尽管如此，它们的功效受到真菌抗性机制的限制，主要是外排泵的过表达。因此,念珠菌病的死亡率令人担忧，为75％。克服外排介导的抗性的一种潜在策略是抑制该过程。Ailanthusaltissima是一种产生几种活性物质的中国树，由于其提取率低，需要寻找治疗念珠菌病的新药，本研究旨在合成赤霉素D及其类似物，以及评估其逆转白色念珠菌耐药表型的能力。香豆素异黄定是通过无溶剂Knoevenagel缩合为关键步骤，通过全合成制备的。Isofraxidin和其他市售香豆素用异戊二烯基或香叶基烷基化，得到天然产物altissimacoumarinD和七个类似物。使用微肉汤方法评估香豆素的抗真菌活性及其逆转真菌抗性表型的能力。使用红细胞和计算机预测评估毒性。所有化合物都通过抑制外排泵提高了氟康唑的抗真菌活性，ACS47和ACS50最为活跃。没有一种香豆素对红细胞有毒。计算机预测表明ACS47和ACS50可能对人类使用是安全的。ACS47和ACS50在用作抗白色念珠菌抗性菌株的抗真菌治疗中的佐剂时是有希望的候选物。
