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

A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action.

• MeSH
• Apoptosis drug effects   MeSH
• DNA metabolism   MeSH
• Doxorubicin pharmacology   MeSH
• HCT116 Cells MeSH
• Intercalating Agents pharmacology   MeSH
• Small Molecule Libraries chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Naphthols chemical synthesis   chemistry   pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Design * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-naphthol MeSH Browser
• calf thymus DNA MeSH Browser
• DNA MeSH
• Doxorubicin MeSH
• Intercalating Agents MeSH
• Small Molecule Libraries MeSH
• Tumor Suppressor Protein p53 MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH

A series of twenty substituted 2-hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(alkoxycarbonyl)amino]benzoates were prepared and characterized. As similar compounds have been described as potential antimycobacterials, primary in vitro screening of the synthesized carbamates was also performed against two mycobacterial species. 2-Hydroxy-3-[2-(2,6-dimethoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, 2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, and 2-hydroxy-3-[2-(2-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride showed higher activity against M. avium subsp. paratuberculosis and M. intracellulare than the standards ciprofloxacin, isoniazid, or pyrazinamide. Cytotoxicity assay of effective compounds was performed using the human monocytic leukaemia THP-1 cell line. Compounds with predicted amphiphilic properties were also tested for their effects on the rate of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. All butyl derivatives significantly stimulated the rate of PET, indicating that the compounds can induce conformational changes in thylakoid membranes resulting in an increase of their permeability and so causing uncoupling of phosphorylation from electron transport.

• MeSH
• Anti-Bacterial Agents chemical synthesis   pharmacology   MeSH
• Benzoates chemical synthesis   pharmacology   MeSH
• Carbamates chemical synthesis   pharmacology   MeSH
• Mycobacterium avium subsp. paratuberculosis drug effects   MeSH
• Uncoupling Agents chemical synthesis   pharmacology   MeSH
• Spinacia oleracea drug effects   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Benzoates MeSH
• Carbamates MeSH
• Uncoupling Agents MeSH

In this study, a series of twenty-two ring-substituted 3-hydroxy-N-phenylnaphthalene-2-carboxanilides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four Staphylococcus strains and against two mycobacterial species. 3-Hydroxy-N-(2-methoxyphenyl)naphthalene-2-carboxamide showed high biological activity (MIC = 55.0 µmol/L) against S. aureus as well as methicillin-resistant strains. N-(2-Fluorophenyl)-3-hydroxynaphthalene-2-carboxamide showed higher activity (MIC = 28.4 µmol/L) against M. marinum than the standard isoniazid and 3-hydroxy-N-(4-nitrophenyl)naphthalene-2-carboxamide expressed higher activity (MIC = 13.0 µmol/L) against M. kansasii than the standard isoniazid. Cytotoxicity assay of effective antimicrobial compounds was performed using the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide was 16.9 μmol/L. The structure-activity relationships of all compounds are discussed.

• MeSH
• Anti-Bacterial Agents chemical synthesis   pharmacology   MeSH
• Chloroplasts drug effects   MeSH
• Photosynthesis drug effects   MeSH
• Herbicides chemical synthesis   pharmacology   MeSH
• Hydrazines chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Spinacia oleracea drug effects   MeSH
• Staphylococcus aureus drug effects   MeSH
• Electron Transport drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Herbicides MeSH
• Hydrazines MeSH

A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(₃,₄) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(₄) exhibited slightly more effective AChE inhibitors than in C'(₃). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Electrophorus metabolism   MeSH
• Phenylcarbamates metabolism   MeSH
• Galantamine metabolism   MeSH
• Carbamates chemistry   pharmacology   MeSH
• Catalytic Domain MeSH
• Models, Molecular MeSH
• Rivastigmine MeSH
• Salicylanilides chemistry   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Binding Sites MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Phenylcarbamates MeSH
• Galantamine MeSH
• Carbamates MeSH
• Rivastigmine 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

The resistance to antimicrobial agents brings a need of novel antimicrobial agents. We have synthesized and found the in vitro antibacterial activity of salicylanilide esters with benzoic acid (2-(phenylcarbamoyl)phenyl benzoates) in micromolar range. They were evaluated in vitro for the activity against eight fungal and eight bacterial species. All derivatives showed a significant antibacterial activity against Gram-positive strains with minimum inhibitory concentrations ≥ 0.98 μmol/L including methicillin-resistant Staphylococcus aureus strain. The most active compounds were 5-chloro-2-(3,4-dichlorophenylcarbamoyl)phenyl benzoate and 4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl benzoate. The antifungal activity is significantly lower.

• MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Antifungal Agents pharmacology   MeSH
• Benzoates pharmacology   MeSH
• Magnetic Resonance Spectroscopy MeSH
• Microbial Sensitivity Tests MeSH
• Salicylanilides pharmacology   MeSH
• Spectrophotometry, Infrared MeSH
• In Vitro Techniques MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Antifungal Agents MeSH
• Benzoates MeSH
• salicylanilide MeSH Browser
• Salicylanilides MeSH

In this study, a series of twenty-two 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides and ten 4-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides is described. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against mycobacterial, bacterial and fungal strains. They were also evaluated for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The compounds showed biological activity comparable with or higher than the standards isoniazid, fluconazole, penicillin G or ciprofloxacin. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.

• MeSH
• Anti-Bacterial Agents chemistry   pharmacology   MeSH
• Benzamides chemistry   pharmacology   MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium drug effects   MeSH
• Electron Transport MeSH
• Chromatography, High Pressure Liquid MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Benzamides MeSH

In this study, a series of twelve ring-substituted salicylanilides and carbamoylphenylcarbamates were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Moreover, their site of action in the photosynthetic apparatus was determined. Primary in vitro screening of the synthesized compounds was also performed against mycobacterial, bacterial and fungal strains. Several compounds showed biological activity comparable with or higher than the standards 3-(3,4-dichlorophenyl)-1,1-dimethylurea, isoniazid, penicillin G, ciprofloxacin or fluconazole. The most active compounds showed minimal anti-proliferative activity against human cells in culture, indicating they would have low cytotoxicity. For all compounds, the relationships between lipophilicity and the chemical structure are discussed.

• MeSH
• Absidia drug effects   MeSH
• Anti-Bacterial Agents chemical synthesis   chemistry   pharmacology   MeSH
• Antifungal Agents chemical synthesis   chemistry   pharmacology   MeSH
• Chloroplasts drug effects   metabolism   MeSH
• Phenylcarbamates chemical synthesis   chemistry   pharmacology   MeSH
• Photosynthesis drug effects   MeSH
• Herbicides chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Salicylanilides chemical synthesis   chemistry   pharmacology   MeSH
• Spinacia oleracea drug effects   metabolism   MeSH
• Staphylococcus aureus drug effects   MeSH
• Staphylococcus epidermidis drug effects   MeSH
• Electron Transport drug effects   MeSH
• Trichophyton drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Antifungal Agents MeSH
• Phenylcarbamates MeSH
• Herbicides MeSH
• Salicylanilides MeSH