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Volume 12
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10.3390/biomedicines12071621
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Article

Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives

by
Jingyi Ma
1,†,
Dileepkumar Veeragoni
2,†,
Hindole Ghosh
2,
Nicole Mutter
3,
Gisele Barbosa
3,
Lauren Webster
3,
Rainer Schobert
4,
Wendy van de Sande
1,*,
Prasad Dandawate
2,* and
Bernhard Biersack
4,*
1
Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
2
Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
3
Wellcome Centre—Antiinfectives Research, School of Life Sciences, University of Dundee, Nethergate, Dundee DD1 4HN, UK
4
Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomedicines 2024, 12(7), 1621; https://doi.org/10.3390/biomedicines12071621
Submission received: 25 June 2024 / Revised: 12 July 2024 / Accepted: 19 July 2024 / Published: 21 July 2024
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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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.
Keywords: niclosamide; salicylanilide; fluorine; anticancer agents; antifungal agents; esophageal carcinoma; eumycetoma; STAT3; β-catenin; Madurella mycetomatis niclosamide; salicylanilide; fluorine; anticancer agents; antifungal agents; esophageal carcinoma; eumycetoma; STAT3; β-catenin; Madurella mycetomatis

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MDPI and ACS Style

Ma, J.; Veeragoni, D.; Ghosh, H.; Mutter, N.; Barbosa, G.; Webster, L.; Schobert, R.; Sande, W.v.d.; Dandawate, P.; Biersack, B. Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives. Biomedicines 2024, 12, 1621. https://doi.org/10.3390/biomedicines12071621

AMA Style

Ma J, Veeragoni D, Ghosh H, Mutter N, Barbosa G, Webster L, Schobert R, Sande Wvd, Dandawate P, Biersack B. Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives. Biomedicines. 2024; 12(7):1621. https://doi.org/10.3390/biomedicines12071621

Chicago/Turabian Style

Ma, Jingyi, Dileepkumar Veeragoni, Hindole Ghosh, Nicole Mutter, Gisele Barbosa, Lauren Webster, Rainer Schobert, Wendy van de Sande, Prasad Dandawate, and Bernhard Biersack. 2024. "Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives" Biomedicines 12, no. 7: 1621. https://doi.org/10.3390/biomedicines12071621

APA Style

Ma, J., Veeragoni, D., Ghosh, H., Mutter, N., Barbosa, G., Webster, L., Schobert, R., Sande, W. v. d., Dandawate, P., & Biersack, B. (2024). Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives. Biomedicines, 12(7), 1621. https://doi.org/10.3390/biomedicines12071621

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