Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human and veterinary medicine as anthelmintics, have recently emerged as candidates for drug repurposing in oncology. The most prominent example of salicylanilide anthelmintic, that is intensively studied for its potential anticancer properties, is niclosamide. Nevertheless, recent studies have discovered extensive anticancer potential in a number of other salicylanilides. This potential of their anticancer action is mediated most likely by diverse mechanisms of action such as uncoupling of oxidative phosphorylation, inhibition of protein tyrosine kinase epidermal growth factor receptor, modulation of different signaling pathways as Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways or induction of B-Raf V600E inhibition. Here we provide a comprehensive overview of the current knowledge about the proposed mechanisms of action of anticancer activity of salicylanilides based on preclinical in vitro and in vivo studies, or structural requirements for such an activity.

• Keywords
• STAT3, TK EGFR, anticancer properties, drug repurposing, mitochondrial uncoupling, niclosamide, salicylanilides,
• MeSH
• Anthelmintics * pharmacology   MeSH
• Humans MeSH
• Niclosamide pharmacology   MeSH
• Salicylanilides * pharmacology   chemistry   MeSH
• Signal Transduction MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Anthelmintics * MeSH
• Niclosamide MeSH
• Salicylanilides * MeSH

Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF3 at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties.

• Keywords
• antiproliferative effect, apoptosis, cell cycle, hydroxynaphthalene carboxamides, salicylanilides,
• MeSH
• Anilides chemistry   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• MCF-7 Cells MeSH
• Mitochondria drug effects   metabolism   MeSH
• Molecular Structure MeSH
• Naphthols chemistry   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Salicylanilides chemistry   pharmacology   MeSH
• Superoxides metabolism   MeSH
• THP-1 Cells MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anilides MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• salicylanilide MeSH Browser
• Salicylanilides MeSH
• Superoxides MeSH

The development of novel antimicrobial agents represents a timely research topic. Eighteen salicylanilide 4-(trifluoromethyl)benzoates were evaluated against Mycobacterium tuberculosis, M. avium and M. kansasii, eight bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and for the inhibition of mycobacterial isocitrate lyase. Some compounds were further screened against drug-resistant M. tuberculosis and for their cytotoxicity. Minimum inhibitory concentrations (MICs) for all mycobacterial strains were within 0.5-32 μmol/L, with 4-chloro-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-(trifluoromethyl)benzoate superiority. Gram-positive bacteria including MRSA were inhibited with MICs ³ 0.49 μmol/L, while Gram-negative ones were much less susceptible. Salicylanilide 4-(trifluoromethyl)benzoates showed significant antibacterial properties, for many strains being comparable to standard drugs (isoniazid, benzylpenicillin) with no cross-resistance. All esters showed mild inhibition of mycobacterial isocitrate lyase and four compounds were comparable to 3-nitropropionic acid without a direct correlation between in vitro MICs and enzyme inhibition.

• MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Benzoates pharmacology   MeSH
• Nitro Compounds pharmacology   MeSH
• Isocitrate Lyase antagonists & inhibitors   metabolism   MeSH
• Methicillin-Resistant Staphylococcus aureus drug effects   MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium avium drug effects   MeSH
• Mycobacterium kansasii drug effects   MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Propionates pharmacology   MeSH
• Salicylanilides pharmacology   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 3-nitropropionic acid MeSH Browser
• Anti-Bacterial Agents MeSH
• Benzoates MeSH
• Nitro Compounds MeSH
• Isocitrate Lyase MeSH
• Propionates MeSH
• salicylanilide MeSH Browser
• Salicylanilides MeSH

Searching for novel antimicrobial agents still represents a current topic in medicinal chemistry. In this study, the synthesis and analytical data of eighteen salicylanilide esters with 4-(trifluoromethyl)benzoic acid are presented. They were assayed in vitro as potential antimycotic agents against eight fungal strains, along with their parent salicylanilides. The antifungal activity of the presented derivatives was not uniform and moulds showed a higher susceptibility with minimum inhibitory concentrations (MIC) ≥ 0.49 µmol/L than yeasts (MIC ≥ 1.95 µmol/L). However, it was not possible to evaluate a range of 4-(trifluoromethyl)benzoates due to their low solubility. In general, the most active salicylanilide was N-(4-bromophenyl)-4-chloro-2-hydroxybenzamide and among esters, the corresponding 2-(4-bromophenylcarbamoyl)-5-chlorophenyl 4-(trifluoromethyl) benzoate exhibited the lowest MIC of 0.49 µmol/L. However, the esterification of salicylanilides by 4-(trifluoromethyl)benzoic acid did not result unequivocally in a higher antifungal potency.

• MeSH
• Absidia drug effects   MeSH
• Antifungal Agents chemical synthesis   pharmacology   MeSH
• Aspergillus fumigatus drug effects   MeSH
• Benzoates chemical synthesis   pharmacology   MeSH
• Candida drug effects   MeSH
• Esterification MeSH
• Esters MeSH
• Microbial Sensitivity Tests MeSH
• Salicylanilides chemical synthesis   pharmacology   MeSH
• Toluene analogs & derivatives   chemistry   MeSH
• Trichophyton drug effects   MeSH
• Trichosporon drug effects   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 4-(trifluoromethyl)benzoic acid MeSH Browser
• Antifungal Agents MeSH
• Benzoates MeSH
• Esters MeSH
• Salicylanilides MeSH
• Toluene MeSH