Pharmacologically active salicylanilides (2-hydroxy-N-phenylbenzamides) have been a promising area of interest in medicinal chemistry-related research for quite some time. This group of compounds has shown a wide spectrum of biological activities, including but not limited to anticancer effects. In this study, substituted salicylanilides were chosen to evaluate the in vitro activity on U87 human glioblastoma (GBM) cells. The parent salicylanilide, salicylanilide 5-chloropyrazinoates, a 4-aminosalicylic acid derivative, and the new salicylanilide 4-formylbenzoates were chemically and in vitro characterized. To enhance the internalization of the compounds, they were conjugated to delivery peptides with the formation of oxime bonds. Oligotuftsins ([TKPKG]n, n = 1-4), the ligands of neuropilin receptors, were used as GBM-targeting carrier peptides. The in vitro cellular uptake, intracellular localization, and penetration ability on tissue-mimicking models of the fluorescent peptide derivatives were determined. The compounds and their peptide conjugates significantly decreased the viability of U87 glioma cells. Salicylanilide compound-induced GBM cell death was associated with activation of autophagy, as characterized by immunodetection of autophagy-related processing of light chain 3 protein.

• Publikační typ
• časopisecké články MeSH

A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF3-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC50 ranged from 1.4 to >10 µM and increased with increasing lipophilicity.

• Klíčová slova
• antimicrobial activity, cytotoxicity, lipophilicity, peptidomimetics, salicylamide, structure–activity relationships,
• MeSH
• ampicilin MeSH
• anilidy MeSH
• antibakteriální látky farmakologie   MeSH
• benzamidy MeSH
• isoniazid MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus * MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis * MeSH
• peptidomimetika * MeSH
• salicylanilidy farmakologie   MeSH
• vankomycin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ampicilin MeSH
• anilidy MeSH
• antibakteriální látky MeSH
• benzamidy MeSH
• isoniazid MeSH
• peptidomimetika * MeSH
• salicylanilide MeSH Prohlížeč
• salicylanilidy MeSH
• vankomycin MeSH

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.

• Klíčová slova
• InhA, antimycobacterial activity, enzyme inhibition, esters, isoniazid, mechanism of action, mutual prodrugs,
• Publikační typ
• časopisecké články MeSH

A series of thirty-one hydrazones of aminoguanidine, nitroaminoguanidine, 1,3-diaminoguanidine, and (thio)semicarbazide were prepared from various aldehydes, mainly chlorobenzaldehydes, halogenated salicylaldehydes, 5-nitrofurfural, and isatin (yields of 50-99%). They were characterized by spectral methods. Primarily, they were designed and evaluated as potential broad-spectrum antimicrobial agents. The compounds were effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus with minimum inhibitory concentrations (MIC) from 7.8 µM, as well as Gram-negative strains with higher MIC. Antifungal evaluation against yeasts and Trichophyton mentagrophytes found MIC from 62.5 µM. We also evaluated inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The compounds inhibited both enzymes with IC50 values of 17.95-54.93 µM for AChE and ≥1.69 µM for BuChE. Based on the substitution, it is possible to modify selectivity for a particular cholinesterase as we obtained selective inhibitors of either AChE or BuChE, as well as balanced inhibitors. The compounds act via mixed-type inhibition. Their interactions with enzymes were studied by molecular docking. Cytotoxicity was assessed in HepG2 cells. The hydrazones differ in their toxicity (IC50 from 5.27 to >500 µM). Some of the derivatives represent promising hits for further development. Based on the substitution pattern, it is possible to modulate bioactivity to the desired one.

• Klíčová slova
• acetylcholinesterase, aminoguanidine, antimicrobial activity, butyrylcholinesterase, cytotoxicity, enzyme inhibition, hydrazones, molecular docking, salicylaldehydes,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• antiproliferative effect, apoptosis, cell cycle, hydroxynaphthalene carboxamides, salicylanilides,
• MeSH
• anilidy chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• MFC-7 buňky MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• naftoly chemie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• salicylanilidy chemie   farmakologie   MeSH
• superoxidy metabolismus   MeSH
• THP-1 buňky MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• naftoly MeSH
• protinádorové látky MeSH
• reaktivní formy kyslíku MeSH
• salicylanilide MeSH Prohlížeč
• salicylanilidy MeSH
• superoxidy MeSH

The development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer's disease. Thirty-six halogenated 2-hydroxy-N-phenylbenzamides (salicylanilides) with various substitution patterns and their esters with phosphorus-based acids were synthesized in yields of 72% to 92% and characterized. They were evaluated for in vitro inhibition of AChE from electric eel and BuChE from equine serum using modified Ellman's spectrophotometric method. The benzamides exhibited a moderate inhibition of AChE with IC50 values in a narrow concentration range from 33.1 to 85.8 µM. IC50 values for BuChE were higher (53.5-228.4 µM). The majority of derivatives inhibit AChE more efficiently than BuChE and are comparable or superior to rivastigmine-an established cholinesterases inhibitor used in the treatment of Alzheimer's disease. Phosphorus-based esters especially improved the activity against BuChE with 5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl diethyl phosphite 5c superiority (IC50 = 2.4 µM). This derivative was also the most selective inhibitor of BuChE. It caused a mixed inhibition of both cholinesterases and acted as a pseudo-irreversible inhibitor. Several structure-activity relationships were identified, e.g., favouring esters and benzamides obtained from 5-halogenosalicylic acids and polyhalogenated anilines. Both 2-hydroxy-N-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.

• Klíčová slova
• acetylcholinesterase, benzamides, butyrylcholinesterase, enzyme inhibition, esters, in vitro inhibition, phosphorus derivatives, salicylanilides,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• benzamidy chemie   farmakologie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• Electrophorus MeSH
• estery chemie   farmakologie   MeSH
• fosfor chemie   MeSH
• inhibiční koncentrace 50 MeSH
• koně MeSH
• molekulární struktura MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• benzamidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• estery MeSH
• fosfor 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
• apoptóza účinky léků   MeSH
• DNA metabolismus   MeSH
• doxorubicin farmakologie   MeSH
• HCT116 buňky MeSH
• interkalátory farmakologie   MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• naftoly chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-naphthol MeSH Prohlížeč
• calf thymus DNA MeSH Prohlížeč
• DNA MeSH
• doxorubicin MeSH
• interkalátory MeSH
• knihovny malých molekul MeSH
• nádorový supresorový protein p53 MeSH
• naftoly MeSH
• protinádorové látky MeSH

Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R² = Me; 2i: R² = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-ylbenzamides with hydroxy substitution (2b: R² = 2-OH; 2d: R² = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.

• Klíčová slova
• antibacterial, antifungal, antimycobacterial, cytotoxicity, linker, pyrazinamide, retro-amide, tuberculosis,
• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• benzamidy chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• racionální návrh léčiv * MeSH
• techniky syntetické chemie * MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• benzamide MeSH Prohlížeč
• benzamidy MeSH

Series of thirteen 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl carbamates and thirteen 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl carbamates with alkyl/cycloalkyl/arylalkyl chains were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, two methicillin-resistant S. aureus strains, Mycobacterium marinum, and M. kansasii. 1-[(2-Chlorophenyl)carbamoyl]naphthalen-2-yl ethylcarbamate and 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl ethylcarbamate showed antistaphylococcal (MICs = 42 µM against MRSA) and antimycobacterial (MICs = 21 µM) activity against the tested strains comparable with or higher than that of the standards ampicillin and isoniazid. In the case of bulkier carbamate tails (R > propyl/isopropyl), the activity was similar (MICs ca. 70 µM). Screening of the cytotoxicity of both of the most effective compounds was performed using THP-1 cells, and no significant lethal effect was observed (LD50 >30 µM). The structure-activity relationships are discussed.

• Klíčová slova
• carbamates, hydroxynaphthalene-carboxamides, in vitro antibacterial activity, in vitro antimycobacterial activity, in vitro cytotoxicity assay, structure-activity relationships,
• MeSH
• antiinfekční látky * chemická syntéza   chemie   farmakologie   MeSH
• cytotoxiny * chemická syntéza   chemie   farmakologie   MeSH
• karbamáty * chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus růst a vývoj   MeSH
• Mycobacterium tuberculosis růst a vývoj   MeSH
• nádorové buněčné linie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiinfekční látky * MeSH
• cytotoxiny * MeSH
• karbamáty * MeSH

A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their nineteen positional isomers N-(alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides were prepared and characterized. Primary in vitro screening of all the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. kansasii and M. smegmatis. Screening of the cytotoxicity of the compounds was performed using human monocytic leukemia THP-1 cells. Some of the tested compounds showed antimycobacterial activity comparable with or higher than that of rifampicin. For example, 2-hydroxy-N-(4-propoxyphenyl)-naphthalene-1-carboxamide showed the highest activity (MIC = 12 µM) against M. tuberculosis with insignificant cytotoxicity. N-[3-(But-2-yloxy)phenyl]- and N-[4-(but-2-yloxy)phenyl]-2-hydroxy-naphthalene-1-carboxamide demonstrated high activity against all tested mycobacterial strains and insignificant cytotoxicity. N-(Alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides demonstrated rather high effect against M. smegmatis and M. kansasii and strong antiproliferative effect against the human THP-1 cell line. Lipophilicity was found as the main physicochemical parameter influencing the activity. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Structure-activity relationships are discussed.

• Klíčová slova
• MTT assay, hydroxynaphthalenecarboxamides, in vitro antimycobacterial activity, lipophilicity, structure-activity relationships,
• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mikrobiální viabilita účinky léků   MeSH
• molekulární struktura MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Mycobacterium smegmatis účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• naftoly chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• naftoly MeSH