对真菌感染有限的治疗选择以及对抗真菌药物（尤其是念珠菌属）产生耐药菌株的增多，需要开发新的抗真菌药物和策略。组蛋白去乙酰化酶抑制剂（HDACi），如沃诺斯塔（vorinostat），在癌症治疗中得到了研究，并具有抗真菌作用，可单独或与经典抗真菌药物协同作用。本研究探讨了基于沃诺斯塔结构的两种新型可持续性HDACi（LDT化合物）的抗真菌活性。在对接模拟中，所有分析的HDACi能够结合到念珠菌属、热带念珠菌属和新生隐球菌属的I类HDACs上，这些菌株的形状与沃诺斯塔的结合相似。LDT化合物在单独对真菌进行测试时显示出中等活性，但与抗真菌酮类药物协同作用时显示出更好的活性。在C. albicans（4 µg/mL）中，它们将生物膜形成减少了超过50%，主要作用于真菌的丝状菌丝化。我们评估了LDT化合物对RAW264.7细胞的细胞毒性，发现LDT536仅在浓度达到200 µmol/L时具有细胞毒性，而LDT537的IC50值为29.12 µmol/L。我们的数据表明，这些可持续性和廉价的HDACi具有潜在的抗真菌和抗生物膜活性，其结果优于沃诺斯塔，但需要进一步研究以更好地了解其对真菌细胞的作用机制。© 作者团队2023年。由牛津大学出版社代表国际人类和动物真菌学学会（The International Society for Human and Animal Mycology）发表。

The limited therapeutic options for fungal infections and the increased incidence of fungal strains resistant to antifungal drugs, especially Candida spp., require the development of new antifungal drugs and strategies. Histone deacetylase inhibitors (HDACi), like vorinostat, have been studied in cancer treatment and have antifungal effects, acting alone or synergistically with classical antifungals. Here we investigated the antifungal activity of two novel sustainable HDACi (LDT compounds) based on vorinostat structure. In docking simulations, all HDACi analyzed can bind to Class-I HDACs of Candida albicans, Candida tropicalis, and Cryptococcus neoformans, which have similar shapes to vorinostat binding. LDT compounds showed moderate activity when tested alone against fungi but act synergistically with antifungal azoles against Candida spp. They reduced biofilm formation by more than 50% in C. albicans (4 µg/mL), with the main action in fungal filamentation. Cytotoxicity of the LDT compounds against RAW264.7 cells was evaluated and LDT536 demonstrated cytotoxicity only at the concentration of 200 µmol/L, while LDT537 showed IC50 values of 29.12 µmol/L. Our data indicated that these sustainable and inexpensive HDACi have potential antifungal and antibiofilm activities, with better results than vorinostat, although further studies are necessary to better understand the mechanism against fungal cells.© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.