Vulvovaginal candidiasis (VVC) affects millions of women around the world every year. Candida albicans is the most frequently isolated pathogen in women and its rapid ability to develop resistance to first and second line therapies has boosted the search for new and effective antifungal agents. In this study, we show the in vitro anti-Candida activity of fifteen synthetic chalcone analogs and their antifungal potential in an in vivo model of VVC. Chalcone 12 showed potent antifungal effects, being able to inhibit the growth of Candida spp. at a concentration of 15.6 µg mL^-1. In addition, mechanism of action studies have indicated the ergosterol fungal membrane as the target of this compound. Despite a considerable antifungal activity, the chalcone 12 showed high cytotoxicity in kidney cells lineages. Moreover, this compound was able to reduce Candida-associated virulence, impairing yeast-hyphal transition in C. albicans. An in vivo model of VVC showed that chalcone 12 significantly reduces the fungal load. Taken together, these findings showed that the chalcone 12 is a potent anti-Candida agent in vitro beyond of contribute to improve the fungal infection in a model of CVV. However, it showed low selectivity and high toxicity, suggesting molecular modifications to minimize these proprieties.

中文翻译：

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查尔酮衍生物作为潜在的抗念珠菌制剂的设计，合成，生物学活性和构效关系研究。

外阴念珠菌病（VVC）每年都会影响全球数百万妇女。白色念珠菌是女性中最常见的病原体，其对一线和二线疗法产生抗药性的快速能力促进了对新的有效抗真菌剂的寻找。在这项研究中，我们显示了十五种合成查尔酮类似物的体外抗念珠菌活性及其在VVC体内模型中的抗真菌潜力。查耳酮12具有较强的抗真菌作用，能够抑制假丝酵母菌的生长。浓度为15.6 µg mL ^-1。另外，作用机理研究表明麦角固醇真菌膜是该化合物的靶标。尽管具有相当大的抗真菌活性，查耳酮12在肾细胞谱系中显示出高细胞毒性。此外，该化合物能够减少念珠菌相关的毒力，损害白色念珠菌中的酵母-菌丝过渡。VVC的体内模型显示查尔酮12大大降低了真菌的负荷。综上所述，这些发现表明查耳酮12是体外有效的抗念珠菌剂，除了在CVV模型中有助于改善真菌感染外。然而，它显示出低选择性和高毒性，表明分子修饰以最小化这些特性。