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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.

A series of twelve nature-inspired 3,4,5-trimethoxycinnamates were prepared and characterized. All compounds, including the starting 3,4,5-trimethoxycinnamic acid, were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, the selectivity index (SI) was also determined. 2-Fluororophenyl (2E)-3-(3,4,5-trimethoxyphenyl)-prop-2-enoate demonstrated the highest SI (1.71) in favor of BChE inhibition. 2-Chlorophenyl (2E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoate showed the highest AChE-inhibiting (IC50 = 46.18 µM) as well as BChE-inhibiting (IC50 = 32.46 µM) activity with an SI of 1.42. The mechanism of action of the most potent compound was determined by the Lineweaver–Burk plot as a mixed type of inhibition. An in vitro cell viability assay confirmed the insignificant cytotoxicity of the discussed compounds on the two cell lines. Trends between structure, physicochemical properties and activity were discussed.

A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron&reg, respectively. Generally, most compounds exhibited better inhibition potency towards AChE, however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure&ndash, activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity&ndash, activity landscape index for BChE inhibitory response values. The &lsquo, indirect&rsquo, ligand-based and &lsquo, direct&rsquo, protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an &lsquo, average&rsquo, 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).

The paper deals with a novel flame retardant and its application in waterborne coatings. The flame retardant was synthesized from hexachloro-cyclo-triphosphazene by nucleophilic substitution with allylamine. Functionalized emulsion copolymers bearing in the structure hexaallylamino-cyclo-triphosphazene were prepared by the semicontinuous emulsion polymerization. The latexes were used as the main component of transparent coating systems cured by melamine formaldehyde resin. The incorporation hexaallylamino-cyclo-triphosphazene did not affect transparency, flexibility, and toughness of resulting coatings and increased their flame stability in terms of the amount of smoke release and maximum average rate of heat emission indicating a slower flame spread during the material combustion.

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase, however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure&ndash, activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host&ndash, target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199–25 µM) comparable to or more potent than ampicillin and ciprofloxacin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the highest potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotoxicity of the most effective compounds was performed using human monocytic leukemia THP-1 cells, and based on LD50 values, it can be stated that the compounds have insignificant toxicity against human cells.

Series of ten N-substituted 2-(aminoethyl)-6-fluorobenzothiazoles inhibited photosynthetic electron transport in spinach chloroplasts. The inhibitory activity linearly increased with hydrophobic contributions (expressed as hydrophobic constants π) and molar volumes of individual substituents in C(2) position of 6-fluorobenzothiazole scaffold to the optima π ca. 2 and MV ca. 233 cm3, while for more lipophilic and/or bulkier derivatives PET inhibiting activity linearly decreased. The site of inhibitory action of the tested compounds is situated on the donor side of photosystem II, and interaction of these compounds with aromatic amino acid residues in photosynthetic proteins was confirmed by fluorescence spectroscopy. Synthesis and characterization of five new Nα-(alkoxycarbonyl)-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-l-phenylalaninamides is presented as well.

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.

Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

This study examined the antibacterial properties of nineteen benzoxazole, isoniazid, ethionamide and salicylanilide derivatives against Staphylococcus aureus (S. aureus). It was found that three salicylanilide-derived compounds demonstrated antistaphylococcal activity: 5-Chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (5-Cl-4'-CF3- SAL), 4-chloro-2-(3-chlorophenylcarbamyoyl)phenyl)-2-(benzyloxycarbonylamino)propanoate (AIM31) and 4-chloro-2- (4-(trifluoromethyl)phenylcarbamoyl)phenyl acetate (AIM33). Investigation of the chemical structures of these three compounds and comparison with a non-inhibitory salicylanilide compound (i.e. 5,3'-diCl-SAL) illustrated that different combinations of chemical groups at defined positions on the salicylanilide core structure had a marked influence on antistaphylococcal activity. The most effective compound was AIM33 which inhibited staphylococcal growth and displayed an initial MIC value of 3.12 μg ml(-1) and subsequent investigation revealed that an MIC as low as of 0.5 μg ml(-1) was achievable. In this case, the dual presence of a trifluoromethyl group and an acetylated phenolic hydroxyl to the salicylanilide core structure led to greatly enhanced activity.

Salicylanilides are a well-known family of pharmacological compounds, which are under renewed investigation because of the discovery of novel interesting biological activities and mechanisms of action over the last decade. This comprehensive mini-review de-scribes the biological and pharmacological properties of salicylanilides, their activity against atypical and multi-drug resist ant mycobacte-rial strains, and synthetic routes for their preparation. In particular, this review focuses on the synthesis and biological properties of sali-cylanilides and O -substituted derivates reported between 2000 and 2010, which have displayed the highest antituberculosis or antifungal activity. Keywords: Anti-MDR tuberculotics, anti-tuberculotic agents, hydroxybenzamides, salicylan ilides, salicylanilide derivates. 1. INTRODUCTION Salicylanilides ( N -substituted hydroxy benzamides) are well-known organic pharmacological compounds with numerous bio-logical activities, which were initially investigated for their antimi-crobial [1] and antifungal activities [2], as well as their usefulness as topical antimycotics and antiplaque agents [3]. Salicylanilides have also found use as molluscicidal [4] or anthelmintic agents [5] in human and veterinary practise. The most successful of these, 5,2´-dichloro-4´-nitrosalicylanilide (Niclosamide), is a member of a group of common molluscicides [6] with anthelmintic properties, and is also effective in the treatment of diphyllobothriasis and hy-menolepiasis [7]. Closantel is another broad-spectrum anthelmintic salicylanilide, which has been used as an anti-trematode, anti-nematode and anti-arthropod, in combination with benzimidazole anthelmintics such as Mebendazole [8]. Rafoxanide is highly active against

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.

Tuberculosis remains the leading cause of mortality worldwide even in the 21st century. This review summarises all facts concerning a front-line antituberculotic drug isoniazide – metabolism, mechanism of activity and resistance. The antimycobacterial pharmacophore moiety of isoniazide has been introduced in a number of various types of molecules (about 510 derivatives have been found) to improve their activity against Mycobacteria species, as well as their multidrug-resistant strains. Several Schiff bases, hydrazones, hydrazides and metal complexes of isoniazide have shown very good activity. Various types of the most active isoniazide derivatives classified according to their structure are reported, their lipophilicity has been calculated and structure-activity relationships are discussed. The original new highly active isoniazide prodrug forms prepared at the Faculty of Pharmacy, Charles University, Czech Republic are presented in a separate chapter of the paper.

The aim of our work was to evaluate effect of selected salicylamides on cell viability of sulfate-reducing bacterium Desulfovibrio piger Vib-7 isolated from the human large intestine, as well as to assess antimicrobial activity and biological properties of these compounds.Microbiological, biochemical, biophysical methods, and statistical processing of the results were used.An antimicrobial activity and biological properties of salicylamides against intestinal sulfate-reducing bacteria was studied. Primary in vitro screening of the synthesized selected salicylamides was performed against D. piger Vib-7. Adding 0.37-1.10 µmol.L(-1) (N-(4-bromophenyl)-5-chloro-2-hydroxybenzamide, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide, 5-chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide, 5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide and 4-chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide) caused decrease in biomass accumulation by 8-53, 64-66, 49-50, 82-90, 43-46% compared to control, respectively. The studied compounds completely inhibited the growth of D. piger Vib-7 under the effect of 30 µmol.L(-1). Moreover, addition of the compounds in the culture medium inhibited the process of dissimilation sulfate dose dependently. Treatment with salicylamides led to the bacterial growth inhibition which correlated with the level of inhibition of sulfate reduction. The data on relative survival of D. piger Vib-7 cells and cytotoxicity of salicylamides are consistent to our research in previous series of the biomass accumulation experiments.A significant cytotoxic activity under the influence of salicylamides was determined. These results are consistent with a data on bacterial growth and inhibition process of dissimilation sulfate. The strongest cytotoxic effect of the derivatives was observed in compounds of 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide and 5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide which showed low survival and high toxicity rates.

Novel benzoxazepines were prepared upon esterification of biologically active salicylanilides with some N-protected amino acids. While the desired conjugates of the salicylanilides with the amino acids were obtained when sterically more demanding amino acids were used, benzoxazepines were formed as a result of a seven-exo-trig cyclization in the case of N-protected glycine and alanine. The structures of the products were confirmed by 2D NMR methods, and further transformations of the acyclic conjugates provided additional support for the proposed mechanism of cyclization.

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-resistantStaphylococcus aureus(MRSA) andS. aureusATCC 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 compound1fexhibiting 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.

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.

A series of photosynthetic electron transport (PET) inhibitors from the group of salicylanilide alkylcarbamates was investigated. The compounds were analyzed using RP-HPLC to determine lipophilicity, and their PET inhibition was determined in spinach (Spinacia oleracea L.) chloroplasts. The site of action of the studied compounds is situated at the donor site of photosystem 2 (PS 2). Compounds substituted by chlorine in C'-3 and C'-4 of the aniline ring and the optimal length of the alkyl chain pentyl-heptyl in the carbamate moiety provided the most active PET inhibitors (IC(50) inhibition10 μmol/L). Disubstitution in C'-3,4 by chlorine caused significant PET inhibiting activity decrease. Nevertheless, for all three series of C'-3, C'-4, C'-3,4 compounds, the dependence of PET activity on lipophilicity showed to be quasi-parabolic.

In this study, a series of nine 4-chloro-2-(3,4-dichlorophenylcarbamoyl)phenyl N-alkylcarbamates was prepared. The procedures for synthesis of the compounds are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. For the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed, as well as their structure-activity relationships (SAR).