2,5-Disubstituted 1,3,4-oxadiazoles are privileged versatile scaffolds in medicinal chemistry that have exhibited diverse biological activities. Acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors are used, e.g., to treat dementias and myasthenia gravis. 5-Aryl-1,3,4-oxadiazoles decorated with dodecyl linked via nitrogen, sulfur or directly to this heterocycle have been designed as potential inhibitors of AChE and BChE. They were prepared from commercially available or in-house prepared hydrazides by reaction with dodecyl isocyanate to form hydrazine-1-carboxamides 2 (yields 67-98%) followed by cyclization using p-toluenesulfonyl chloride and triethylamine in 41-100% yields. Thiadiazole isostere was also synthesized. The derivatives were screened for inhibition of AChE and BChE using Ellman's spectrophotometric method. The compounds showed a moderate dual inhibition with IC50 values of 12.8-99.2 for AChE and from 53.1 µM for BChE. All the heterocycles were more efficient inhibitors of AChE. The most potent inhibitor, N-dodecyl-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine 3t, was subjected to advanced reversibility and type of inhibition evaluation. Structure-activity relationships were identified. Many oxadiazoles showed lower IC50 values against AChE than established drug rivastigmine. According to molecular docking, the compounds interact non-covalently with AChE and BChE and block entry into enzyme gorge and catalytic site, respectively.

• Klíčová slova
• 1,3,4-oxadiazole, 1,3,4-thiadiazole, acetylcholinesterase, butyrylcholinesterase, enzyme inhibition, molecular docking,
• Publikační typ
• časopisecké články MeSH

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

• Klíčová slova
• 4-aminosalicylanilides, CoMSA, carbamate synthesis, cholinesterase inhibition, lipophilicity, molecular docking, similarity-activity landscape index,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• analýza hlavních komponent MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   MeSH
• inhibiční koncentrace 50 MeSH
• karbamáty farmakologie   MeSH
• kyselina aminosalicylová chemie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• racionální návrh léčiv MeSH
• rozpouštědla MeSH
• shluková analýza MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu * MeSH
• THP-1 buňky MeSH
• viabilita buněk MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• karbamáty MeSH
• kyselina aminosalicylová MeSH
• ligandy MeSH
• rozpouštědla MeSH

Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C1 to C18) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives were screened for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) via Ellman's method. All the hydrazinecarboxamides revealed a moderate inhibition of both AChE and BuChE, with IC50 values of 27.04-106.75 µM and 58.01-277.48 µM, respectively. Some compounds exhibited lower IC50 for AChE than the clinically used drug rivastigmine. N-Tridecyl/pentadecyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as the most potent and selective inhibitors of AChE. For inhibition of BuChE, alkyl chain lengths from C5 to C7 are optimal substituents. Based on molecular docking study, the compounds may work as non-covalent inhibitors that are placed in a close proximity to the active site triad. The compounds were evaluated against Mycobacterium tuberculosis H37Rv and nontuberculous mycobacteria (M. avium, M. kansasii). Reflecting these results, we prepared additional analogues of the most active carboxamide (n-hexyl derivative 2f). N-Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine (4) exhibited the lowest minimum inhibitory concentrations within this study (MIC ≥ 62.5 µM), however, this activity is mild. All the compounds avoided cytostatic properties on two eukaryotic cell lines (HepG2, MonoMac6).

• Klíčová slova
• 4-(trifluoromethyl)benzohydrazide, acetylcholinesterase inhibition, antimycobacterial activity, butyrylcholinesterase inhibition, cytostatic properties, hydrazides,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antiinfekční látky * chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory * chemická syntéza   chemie   farmakologie   MeSH
• GPI-vázané proteiny metabolismus   MeSH
• imidazoly * chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• Mycobacterium avium růst a vývoj   MeSH
• Mycobacterium kansasii růst a vývoj   MeSH
• Mycobacterium tuberculosis růst a vývoj   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• antiinfekční látky * MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory * MeSH
• GPI-vázané proteiny MeSH
• imidazoly * 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 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®, 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-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The 'indirect' ligand-based and 'direct' 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 'average' 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).

• Klíčová slova
• CoMSA, IVE-PLS, in vitro cholinesterase inhibition, molecular docking, silicon-based carbamates, similarity-activity landscape index,
• MeSH
• butyrylcholinesterasa MeSH
• chloroplasty MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• fotosystém II (proteinový komplex) MeSH
• inhibiční koncentrace 50 MeSH
• karbamáty chemie   farmakologie   MeSH
• křemík chemie   MeSH
• lidé MeSH
• ligandy MeSH
• simulace molekulového dockingu MeSH
• Spinacia oleracea MeSH
• THP-1 buňky účinky léků   MeSH
• transport elektronů účinky léků   MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• fotosystém II (proteinový komplex) MeSH
• karbamáty MeSH
• křemík MeSH
• ligandy MeSH

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⁻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⁻target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

• Klíčová slova
• CoMSA, IVE-PLS, benzene-based carbamates, in vitro cholinesterase inhibition, molecular docking study,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• analýza hlavních komponent MeSH
• benzen chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• Electrophorus MeSH
• inhibiční koncentrace 50 MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• koně MeSH
• ligandy MeSH
• pravděpodobnost MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• benzen MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• karbamáty MeSH
• ligandy MeSH

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.

• Klíčová slova
• CoMSA, IVE-PLS, carbamates, in vitro cholinesterase inhibition, in vitro cytotoxicity assay, molecular docking study, proline,
• MeSH
• acetylcholinesterasa chemie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• katalytická doména MeSH
• molekulární konformace MeSH
• prolin * chemie   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• karbamáty MeSH
• prolin * 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.

• Klíčová slova
• acetylcholinesterase, butyrylcholinesterase, carbamate, enzyme inhibition, salicylanilide, thiocarbamate,
• MeSH
• acetylcholinesterasa chemie   MeSH
• buňky Hep G2 MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• lidé MeSH
• simulace molekulového dockingu MeSH
• thiokarbamáty chemie   toxicita   MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• thiokarbamáty MeSH

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 µM). 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 µM. 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 µM range.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antituberkulotika MeSH
• cholinesterasové inhibitory MeSH

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

• MeSH
• acetylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• katalytická doména MeSH
• lidé MeSH
• oximy chemie   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vodíková vazba MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• oximy MeSH