A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.

• Keywords
• bioassays, carbamates, cholinesterase inhibitors, molecular modeling, sulfonamides, synthesis,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemistry   MeSH
• Carbamates chemical synthesis   chemistry   MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Sulfonamides chemical synthesis   chemistry   MeSH
• Binding Sites MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• BCHE protein, human MeSH Browser
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Carbamates MeSH
• Sulfonamides MeSH

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

• Keywords
• NPC1, Niemann–Pick type C, cholesterol, genetic disorder, lipid metabolism, lysosomal storage disease, neurodegeneration, sphingolipid, sphingolipids, sphingosine kinase, sphingosine kinase (SphK), sphingosine-1-phosphate (S1P),
• MeSH
• Cell Line MeSH
• Cholesterol metabolism   MeSH
• Endosomes metabolism   MeSH
• Cholesterol Esters metabolism   MeSH
• Fibroblasts MeSH
• Phosphotransferases (Alcohol Group Acceptor) metabolism   MeSH
• Intracellular Signaling Peptides and Proteins metabolism   MeSH
• Humans MeSH
• Lysosomes metabolism   MeSH
• Membrane Glycoproteins metabolism   MeSH
• Mice MeSH
• Niemann-Pick Disease, Type C metabolism   physiopathology   MeSH
• Primary Cell Culture MeSH
• Niemann-Pick C1 Protein genetics   metabolism   MeSH
• Sphingolipids metabolism   MeSH
• Sphingosine genetics   metabolism   MeSH
• Protein Transport MeSH
• Carrier Proteins metabolism   MeSH
• Vesicular Transport Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cholesterol MeSH
• Cholesterol Esters MeSH
• Phosphotransferases (Alcohol Group Acceptor) MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Membrane Glycoproteins MeSH
• NPC2 protein, human MeSH Browser
• Niemann-Pick C1 Protein MeSH
• Sphingolipids MeSH
• Sphingosine MeSH
• sphingosine kinase MeSH Browser
• Carrier Proteins MeSH
• Vesicular Transport Proteins 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.

• Keywords
• CoMSA, IVE-PLS, benzene-based carbamates, in vitro cholinesterase inhibition, molecular docking study,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Principal Component Analysis MeSH
• Benzene chemical synthesis   chemistry   pharmacology   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Electrophorus MeSH
• Inhibitory Concentration 50 MeSH
• Carbamates chemical synthesis   chemistry   pharmacology   MeSH
• Horses MeSH
• Ligands MeSH
• Probability MeSH
• Drug Design MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Benzene MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Carbamates MeSH
• Ligands MeSH

Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a-h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log kw values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕM), varied from 2.113 (compound 8e) to 2.930 (compound 8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a-h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a-h were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8a-h were found to be the most promising against M. tuberculosis; a MIC = 8 μM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phen-ylphenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD50 values > 30 μM indicated. The structure-antimycobacterial activity relationships of the analyzed 8a-h series are also discussed.

• Keywords
• Mycobacterium tuberculosis H37Rv, N-arylpiperazines, arylaminoethanols, electronic properties, lipophilicity,
• MeSH
• Antitubercular Agents chemical synthesis   chemistry   pharmacology   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Cell Line, Tumor MeSH
• Piperazines chemical synthesis   chemistry   pharmacology   MeSH
• Spectrum Analysis MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antitubercular Agents MeSH
• Piperazines 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.

• Keywords
• CoMSA, IVE-PLS, carbamates, in vitro cholinesterase inhibition, in vitro cytotoxicity assay, molecular docking study, proline,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Carbamates chemical synthesis   chemistry   pharmacology   MeSH
• Catalytic Domain MeSH
• Molecular Conformation MeSH
• Proline * chemistry   MeSH
• Molecular Docking Simulation MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Carbamates MeSH
• Proline * MeSH

Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 1-Hydroxy-N-phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC50 = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll a and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P680 and plastoquinone QB in the PET chain occurring on the acceptor side of PS II can be suggested as the site of action of the compounds. The structure-activity relationships are discussed.

• Keywords
• hydroxynaphthalene-carboxamides, photosynthetic electron transport (PET) inhibition, spinach chloroplasts, structure-activity relationships,
• MeSH
• Chloroplasts drug effects   metabolism   MeSH
• Photosynthesis drug effects   MeSH
• Photosystem II Protein Complex metabolism   MeSH
• Inhibitory Concentration 50 MeSH
• Naphthols * chemical synthesis   chemistry   pharmacology   MeSH
• Spinacia oleracea drug effects   metabolism   MeSH
• Electron Transport drug effects   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Photosystem II Protein Complex MeSH
• Naphthols * MeSH