- 2-Hydroxy-N-Phenylbenzamides and their esters inhibit acetylcholinesterase and Butyrylcholinesterase
-
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.
- Krátky, Martin,?těpánková, ?árka,Houngbedji, Neto-Honorius,Vosátka, Rudolf,Vor?áková, Katarína,Vin?ová, Jarmila
-
-
- In vitro activity of salicylamide derivatives against vancomycin-resistant enterococci
-
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.
- Pospisilova, Sarka,Michnova, Hana,Kauerova, Tereza,Pauk, Karel,Kollar, Peter,Vinsova, Jarmila,Imramovsky, Ales,Cizek, Alois,Jampilek, Josef
-
p. 2184 - 2188
(2018/05/25)
-
- Novel salicylanilides from 4,5-dihalogenated salicylic acids: Synthesis, antimicrobial activity and cytotoxicity
-
Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent ([sbnd]NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC?=?1–4?μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5–4?μM.
- Paraskevopoulos, Georgios,Monteiro, Sara,Vosátka, Rudolf,Krátky, Martin,Navrátilová, Lucie,Trejtnar, Franti?ek,Stola?íková, Ji?ina,Vin?ová, Jarmila
-
p. 1524 - 1532
(2017/02/18)
-
- Salicylanilide diethyl phosphates as cholinesterases inhibitors
-
Based on the presence of dialkyl phosphate moiety, we evaluated twenty-seven salicylanilide diethyl phosphates (diethyl [2-(phenylcarbamoyl)phenyl] phosphates) for the inhibition of acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.) and butyrylcholinesterase (BChE) from equine serum. Ellman's spectrophotometric method was used. The inhibitory activity (expressed as IC50 values) was compared with that of the established drugs galantamine and rivastigmine. Salicylanilide diethyl phosphates showed significant activity against both cholinesterases with IC50 values from 0.903 to 86.3 μM. IC50s for BChE were comparatively lower than those obtained for AChE. All of the investigated compounds showed higher inhibition of AChE than rivastigmine, and six of them inhibited BChE more effectively than both rivastigmine and galantamine. In general, derivatives of 4-chlorosalicylic acid showed enhanced activity when compared to derivatives of 5-halogenated salicylic acids, especially against BChE. The most effective inhibitor of AChE was O-{5-chloro-2-[(3-bromophenyl)carbamoyl]phenyl} O,O-diethyl phosphate with IC50 of 35.4 μM, which is also one of the most potent inhibitors of BChE. O-{5-Chloro-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphate exhibited in vitro the strongest inhibition of BChE (0.90 μM). Salicylanilide diethyl phosphates act as pseudo-irreversible cholinesterases inhibitors.
- Krtk, Martin,tpnkov, rka,Vorkov, Katarna,Vinov, Jarmila
-
-
- Salicylanilide diethyl phosphates: Synthesis, antimicrobial activity and cytotoxicity
-
A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of 0.5-62.5 μmol/L. Selected salicylanilide diethyl phosphates also inhibit multidrug-resistant tuberculous strains at the concentration of 1 μmol/L. Salicylanilide diethyl phosphates also exhibited mostly the activity against Gram-positive bacteria (MICs ≥1.95 μmol/L), whereas their antifungal activity is significantly lower. The IC50 values for Hep G2 cells were within the range of 1.56-33.82 μmol/L, but there is no direct correlation with MICs for mycobacteria.
- Vin?ová, Jarmila,Kozic, Ján,Krátky, Martin,Stola?íková, Ji?ina,Mandíková, Jana,Trejtnar, Franti?ek,Buchta, Vladimír
-
p. 728 - 737
(2014/01/23)
-
- Diethyl 2-(phenylcarbamoyl)phenyl phosphorothioates: Synthesis, antimycobacterial activity and cholinesterase inhibition
-
A new series of 27 diethyl 2-(phenylcarbamoyl)phenyl phosphorothioates (thiophosphates) was synthesized, characterized by NMR, IR and CHN analyses and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and two strains of Mycobacterium kansasii. The best activity against M. tuberculosis was found for O-{4-bromo-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphorothioate (minimum inhibitory concentration of 4 iM). The highest activity against nontuberculous mycobacteria was exhibited by O-(5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}- phenyl) O,O-diethyl phosphorothioate with MIC values from 16 iM. Prepared thiophosphates were also evaluated against acetylcholinesterase from electric eel and butyrylcholinesterase from equine serum. Their inhibitory activity was compared to that of the known cholinesterases inhibitors galanthamine and rivastigmine. All tested compounds showed a higher (for AChE inhibition) and comparable (for BChE inhibition) activity to that of rivastigmine, with IC50s within the 8.04 to 20.2 iM range.
- Vinsova, Jarmila,Kratky, Martin,Komloova, Marketa,Dadapeer, Echchukattula,Stipankova, Sarka,Voreakova, Katarina,Stolaoikova, Jioina
-
p. 7152 - 7168
(2014/07/08)
-
- Antibacterial activity of salicylanilide 4-(trifluoromethyl)benzoates
-
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. Grampositive bacteria including MRSA were inhibited with MICs ≥ 0.49 μmol/L, while Gramnegative 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.
- Kratky, Martin,Vinsova, Jarmila,Novotna, Eva,Mandikova, Jana,Trejtnar, Frantisek,Stolarikova, Jirina
-
p. 3674 - 3688
(2013/06/05)
-
- New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species
-
Three series of salicylanilides, esters of N-phenylsalicylamides and 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, in total thirty target compounds were synthesized and characterized. The compounds were evaluated against seven bacterial and three mycobacterial strains. The antimicrobial activities of some compounds were comparable or higher than the standards ampicillin, ciprofloxacin or isoniazid. Derivatives 3f demonstrated high biological activity against Staphylococcus aureus (≤0.03 μmol/L), Mycobacterium marinum (≤0.40 μmol/L) and Mycobacterium kansasii (1.58 μmol/L), 3g shows activity against Clostridium perfringens (≤0.03 μmol/L) and Bacillus cereus (0.09 μmol/L), 3h against Pasteurella multocida (≤0.03 μmol/L) and M. kansasii (≤0.43 μmol/L), 3i against methicillin-resistant S. aureus and B. cereus (≤0.03 μmol/L). The structure-activity relationships are discussed for all the compounds.
- Pauk, Karel,Zadrazilova, Iveta,Imramovsky, Ales,Vinsova, Jarmila,Pokorna, Michaela,Masarikova, Martina,Cizek, Alois,Jampilek, Josef
-
p. 6574 - 6581
(2013/10/22)
-
- Antifungal activity of salicylanilides and their esters with 4-(trifluoromethyl)benzoic acid
-
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.
- Kratky, Martin,Vinsova, Jarmila
-
p. 9426 - 9442
(2012/11/14)
-
- Antimycobacterial assessment of salicylanilide benzoates including multidrug-resistant tuberculosis strains
-
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.
- Kratky, Martin,Vinsova, Jarmila,Stolarikova, Jirina
-
p. 12812 - 12820
(2013/02/23)
-
- New amino acid esters of salicylanilides active against MDR-TB and other microbes
-
Eleven halogenated (S)-2-(phenylcarbamoyl)phenyl 2-acetamido-3- phenylpropanoates (3a-3k) were designed and synthesized as potential antimicrobial agents. They were evaluated in vitro against some mycobacterial, bacterial and fungal strains. These compounds were active against drug-sensitive and atypical mycobacterial strains with general MIC values from 0.25 to 16 μmol/L. The most active compounds were (S)-4-chloro-2-(4-(trifluoromethyl) phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate (3i) and (S)-4-bromo-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3- phenylpropanoate (3k) which exhibited activity against MDR and XDR-TB strains with MICs from 1 to 2 μmol/L. 3k was shown to be less cytotoxic with higher IC50. Some compounds exhibited low MICs on Gram-positive bacteria (MICs ≥ 0.98 μmol/L) and on fungi (MICs ≥ 3.9 μmol/L).
- Krátky, Martin,Vin?ová, Jarmila,Buchta, Vladimír,Horvati, Kata,B?sze, Szilvia,Stola?íková, Ji?ina
-
experimental part
p. 6106 - 6113
(2011/01/13)
-
- Relationship between the structure and antimycobacterial activity of substituted salicylanilides
-
A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3′ and 4′ was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium
- Waisser, Karel,Bures, Otakar,Holy, Pavel,Kunes, Jiri,Oswald, Radek,Jiraskova, Lucie,Pour, Milan,Klimesova, Vera,Kubicova, Lenka,Kaustova, Jarmila
-
-