PDF(Pubmed)
Abstract：
The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8-1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2-0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs.
摘要：
批准的驱虫性水杨酸酰苯胺药物氯硝柳胺已显示出有希望的抗癌和抗菌活性。在这项研究中,具有三氟甲基的新的氯硝柳胺衍生物，三氟甲基硫基，制备了取代氯硝柳胺硝基的五氟硫基取代基（包括两种有前途的水杨酰苯胺的乙醇胺盐），并测试了它们对食管腺癌（EAC）细胞的抗癌活性。此外,抗真菌活性对一组的Madurellamycetomatis菌株，被忽视的热带病Eumycetoma最丰富的病原体，进行了评估。新化合物对EAC和真菌细胞的活性高于母体化合物氯硝柳胺。乙醇胺盐3a是对EAC细胞最具活性的化合物（IC50=0.8-1.0µM），其抗癌作用是通过下调抗凋亡蛋白（BCL2和MCL1）以及降低β-catenin水平和STAT3磷酸化来介导的。通过分子对接证实了与后一种因素结合的合理性。化合物2a和2b对M.mycetomatis显示出高的体外抗真菌活性（IC50=0.2-0.3µM），并且对Galleriamellonella幼虫无毒。观察到感染M.cycetomatis的G.melonella幼虫的存活率略有提高。因此，水杨酰苯胺如2a和3a可以成为新的抗癌和抗真菌药物。
