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

The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria, yeasts, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity was determined. Among bacteria, the genus Staphylococcus, including methicillin-resistant S. aureus, showed the highest susceptibility, with minimum inhibitory concentration values from 7.81 µM. The growth of Candida sp. and Trichophyton interdigitale was inhibited at concentrations starting from 1.95 µM. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as the most selective Schiff base for these strains with no apparent cytotoxicity and a selectivity index higher than 16. With respect to M. tuberculosis and M. kansasii that were inhibited within the range of 8 to 250 µM, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide meets the selectivity requirement. In general, dihalogenation of the salicylic moiety improved the antibacterial and antifungal activity but also increased the cytotoxicity, especially with an increasing atomic mass. Some derivatives offer more advantageous properties than the parent sulfadiazine, thus constituting promising hits for further antimicrobial drug development.

• Keywords
• Schiff bases, antibacterial activity, antifungal activity, antimycobacterial activity, cytotoxicity, sulfadiazine, sulfonamides,
• MeSH
• Aldehydes chemical synthesis   pharmacology   MeSH
• Anti-Bacterial Agents chemical synthesis   chemistry   pharmacology   MeSH
• Antifungal Agents chemical synthesis   chemistry   pharmacology   MeSH
• Anti-Infective Agents chemical synthesis   pharmacology   MeSH
• Hep G2 Cells MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Pyrimidines chemical synthesis   pharmacology   MeSH
• Schiff Bases chemical synthesis   pharmacology   MeSH
• Sulfadiazine analogs & derivatives   chemical synthesis   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aldehydes MeSH
• Anti-Bacterial Agents MeSH
• Antifungal Agents MeSH
• Anti-Infective Agents MeSH
• Pyrimidines MeSH
• salicylaldehyde MeSH Browser
• Schiff Bases MeSH
• Sulfadiazine MeSH

Ring-substituted hydroxynaphthanilides are considered as cyclic analogues of salicylanilides, compounds possessing a wide range of pharmacological activities, including promising anticancer properties. The aim of this study was to evaluate the potential anticancer effect of novel nitro-substituted hydroxynaphthanilides with a special focus on structure-activity relationships. The antiproliferative effect was assessed by Water Soluble Tetrazolium Salts-1 (WST-1) assay, and cytotoxicity was evaluated via dye exclusion test. Flow cytometry was used for cell cycle analysis and detection of apoptosis using Annexin V-FITC/PI assay. Protein expression was estimated by Western blotting. Our data indicate that the potential to cause the antiproliferative effect increases with the shift of the nitro substituent from the ortho- to the para-position. The most potent compounds, 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide (2), and 2-hydroxy-N-(4-nitrophenyl)-naphthalene-1-carboxamide (6) showed antiproliferative activity against THP-1 and MCF-7 cancer cells without affecting the proliferation of 3T3-L1 non-tumour cells. Compounds 2 and 6 induced the accumulation of THP-1 and MCF-7 cells in G1 phase associated with the downregulation of cyclin E1 protein levels, while the levels of cyclin B1 were not affected. Moreover, compound 2 was found to exert the pro-apoptotic effect on the THP-1 cells. These results suggest that hydroxynaphthanilides might represent a potential model structure for the development of novel anticancer agents.

• Keywords
• anticancer effect, apoptosis, cell proliferation, hydroxynaphthanilides, salicylanilides,
• MeSH
• Anilides pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Molecular Structure MeSH
• Naphthalenes chemistry   pharmacology   MeSH
• Naphthols pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 2-hydroxy-N-(4-nitrophenyl)naphthalene-1-carboxamide MeSH Browser
• 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide MeSH Browser
• Anilides MeSH
• Naphthalenes MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, carbamate, enzyme inhibition, salicylanilide, thiocarbamate,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Hep G2 Cells MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   toxicity   MeSH
• Inhibitory Concentration 50 MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Molecular Docking Simulation MeSH
• Thiocarbamates chemistry   toxicity   MeSH
• Protein Binding 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
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Thiocarbamates MeSH

A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S)-3-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (1f), N-{(2S)-1-[(4-bromophenyl)amino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g), and 4-chloro-N-{(2S)-1-[(3,4-dichlorophenyl)amino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (1h) was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL) and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count) after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h.

• MeSH
• Anti-Bacterial Agents chemical synthesis   chemistry   pharmacology   MeSH
• Benzamides chemical synthesis   chemistry   pharmacology   MeSH
• Methicillin-Resistant Staphylococcus aureus growth & development   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Benzamides MeSH

Antimycobacterially active salicylanilide diethyl phosphates were evaluated to identify their potential drug target(s) for the inhibition of several mycobacterial enzymes, including isocitrate lyase, L-alanine dehydrogenase (MtAlaDH), lysine ε-aminotransferase, chorismate mutase, and pantothenate synthetase. The enzymes are related to the nongrowing state of Mycobacterium tuberculosis. Salicylanilide diethyl phosphates represent new candidates with significant inhibitory activity especially against L-alanine dehydrogenase. The most active MtAlaDH inhibitor, 5-chloro-2-[(3-chlorophenyl)carbamoyl]phenyl diethyl phosphate, has an IC50 of 4.96 µM and the best docking results. Other mycobacterial enzymes were mostly inhibited by some derivatives but at higher concentrations; isocitrate lyase showed the highest resistance to salicylanilide diethyl phosphates.

• MeSH
• Antitubercular Agents chemistry   MeSH
• Bacterial Proteins * antagonists & inhibitors   chemistry   MeSH
• Enzyme Inhibitors chemistry   MeSH
• Mycobacterium tuberculosis enzymology   MeSH
• Salicylanilides chemistry   MeSH
• Molecular Docking Simulation * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antitubercular Agents MeSH
• Bacterial Proteins * MeSH
• Enzyme Inhibitors MeSH
• Salicylanilides MeSH

In this study, a series of twenty-two ring-substituted 2-hydroxynaphthalene-1‑carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium marinum, M. kasasii, M. smegmatis. and M. avium paratuberculosis. The compounds were also tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 2-Hydroxy-N-phenylnaphthalene-1-carboxanilide and 2-hydroxy-N-(3-trifluoromethylphenyl)naphthalene-1-carboxamide (IC₅₀ = 29 µmol/L) were the most active PET inhibitors. Some of tested compounds showed the antibacterial and antimycobacterial activity against the tested strains comparable or higher than the standards ampicillin or isoniazid. Thus, for example, 2-hydroxy-N-(3-nitrophenyl)naphthalene-1-carboxamide showed MIC = 26.0 µmol/L against methicillin-resistant S. aureus and MIC = 51.9 µmol/L against M. marinum, or 2-hydroxy-N-phenylnaphthalene-1-carboxamide demonstrated MIC = 15.2 µmol/L against M. kansasii. The structure-activity relationships for all compounds are discussed.

• MeSH
• Anti-Bacterial Agents chemistry   pharmacology   MeSH
• Chloroplasts drug effects   metabolism   MeSH
• Photosynthesis drug effects   MeSH
• Herbicides chemistry   pharmacology   MeSH
• Methicillin-Resistant Staphylococcus aureus drug effects   MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium drug effects   MeSH
• Naphthols chemistry   pharmacology   MeSH
• Spinacia oleracea drug effects   metabolism   MeSH
• Electron Transport MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 2-naphthol MeSH Browser
• Anti-Bacterial Agents MeSH
• Herbicides MeSH
• Naphthols 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

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

The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 μmol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.25–2 μmol/L) regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4-(trifluoromethyl)-phenylcarbamoyl]phenyl benzoate (0.25–1 μmol/L). Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides.

• MeSH
• Antitubercular Agents pharmacology   toxicity   MeSH
• Benzoates pharmacology   toxicity   MeSH
• Hep G2 Cells MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Drug Resistance, Multiple, Bacterial MeSH
• Mycobacterium avium drug effects   MeSH
• Mycobacterium kansasii drug effects   MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Salicylanilides pharmacology   toxicity   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antitubercular Agents MeSH
• Benzoates MeSH
• Salicylanilides MeSH