Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives
2024
Jingyi Ma | Dileepkumar Veeragoni | Hindole Ghosh | Nicole Mutter | Gisele Barbosa | Lauren Webster | Rainer Schobert | Wendy van de Sande | Prasad Dandawate | Bernhard Biersack
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 <i>Madurella mycetomatis</i> 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 <b>3a</b> was the most active compound against EAC cells (IC<sub>50</sub> = 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 <b>2a</b> and <b>2b</b> showed high in vitro antifungal activity against <i>M. mycetomatis</i> (IC<sub>50</sub> = 0.2–0.3 µM) and were not toxic to <i>Galleria mellonella</i> larvae. Slight improvements in the survival rate of <i>G. mellonella</i> larvae infected with <i>M. mycetomatis</i> were observed. Thus, salicylanilides such as <b>2a</b> and <b>3a</b> can become new anticancer and antifungal drugs.
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