Despite the rise of new Candida species, Candida albicans tops the list with high morbidity and mortality rates. To tackle this problem there is a need to explore new antifungals that could replace or augment the current treatment options. We previously reported that tosylation of eugenol on hydroxyl group resulted in molecules with enhanced antifungal potency. In line with that work, we synthesized new eugenol tosylate congeners (ETC-1-ETC-7) with different substituents on pendent sulfonyl group and tested their susceptibility against different fluconazole susceptible and resistant C. albicans strains. We evaluated physiology and mode of cell death in response to the most active derivatives by analyzing major apoptotic markers in yeast such as phosphatidylserine externalization, DNA fragmentation, mitochondrial depolarization and decrease in cytochrome c oxidase activity. The results demonstrated that all C. albicans strains were variably susceptible to the test compounds with MIC ranging from 0.125-512 µg/ml, and the most active compounds (ETC-5, ETC-6 and ETC-7) actuate apoptosis and necrosis in Candida cells in a dose-dependent manner via metacaspase-dependent pathway. Furthermore haemolytic assay showed low cytotoxicity effect of these ETCs. Overall the results indicated that ETCs exhibit potential antifungal activity against C. albicans by activating apoptotic and necrotic pathways.

中文翻译：

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细胞凋亡和坏死作为新型抗丁香酚丁子香酚同源物的治疗靶标。

尽管出现了新的念珠菌物种，但白色念珠菌的发病率和死亡率却高居榜首。为了解决这个问题，需要探索可以替代或增加当前治疗选择的新的抗真菌剂。我们先前曾报道丁香酚在羟基上的甲苯磺酸化导致分子具有增强的抗真菌效力。根据这项工作，我们合成了在磺酰基侧基上具有不同取代基的新丁香酚甲苯磺酸盐同类物（ETC-1-ETC-7），并测试了它们对不同的氟康唑敏感和耐药白色念珠菌菌株的敏感性。我们通过分析酵母中的主要凋亡标记物（例如磷脂酰丝氨酸的外在化，DNA片段化，线粒体去极化和细胞色素c氧化酶活性降低。结果表明，所有白色念珠菌菌株均易受测试化合物的影响，MIC范围为0.125-512 µg / ml，活性最高的化合物（ETC-5，ETC-6和ETC-7）可激活细胞凋亡和坏死。念珠菌细胞通过半胱天冬酶依赖性途径呈剂量依赖性。此外，溶血测定显示这些ETC的低细胞毒性作用。总体而言，结果表明，ETC通过激活细胞凋亡和坏死途径，对白念珠菌具有潜在的抗真菌活性。ETC-6和ETC-7）通过metacaspase依赖性途径以剂量依赖性方式激活念珠菌细胞的凋亡和坏死。此外，溶血测定显示这些ETC的低细胞毒性作用。总体而言，结果表明ETC通过激活细胞凋亡和坏死途径，对白念珠菌具有潜在的抗真菌活性。ETC-6和ETC-7）通过metacaspase依赖性途径以剂量依赖性方式激活念珠菌细胞的凋亡和坏死。此外，溶血测定显示这些ETC的低细胞毒性作用。总体而言，结果表明ETC通过激活细胞凋亡和坏死途径，对白念珠菌具有潜在的抗真菌活性。