title: Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.
abstract: 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.
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. martin.kratky@faf.cuni.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Krátký
authors.affiliation: Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic. Sarka.Stepankova@upce.cz.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Štěpánková
authors.affiliation: Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic. Katarina.Vorcakova@upce.cz.
authors.forename: Katarína
authors.initials: K
authors.lastname: Vorčáková
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Marketa.Svarcova@ujep.cz.|Faculty of Science, J. E. Purkinje University, České mládeže 8, 400 96 Ústí nad Labem, Czech Republic. Marketa.Svarcova@ujep.cz.
authors.forename: Markéta
authors.initials: M
authors.lastname: Švarcová
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. vinsova@faf.cuni.cz.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Vinšová
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000737:chemistry* / Q000633:toxicity
chemical_list: D002800:Cholinesterase Inhibitors; D013859:Thiocarbamates; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: acetylcholinesterase; butyrylcholinesterase; carbamate; enzyme inhibition; salicylanilide; thiocarbamate