title: 1,3-substituted imidazolidine-2,4,5-triones: synthesis and inhibition of cholinergic enzymes.
abstract: A series of novel and highly active acetylcholinesterase and butyrylcholinesterase inhibitors derived from substituted benzothiazoles containing an imidazolidine-2,4,5-trione moiety were synthesized and characterized. The molecular structure of 1-(2,6-diisopropyl-phenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-imidazolidine-2,4,5-trione (3g) was determined by single-crystal X-ray diffraction. Both optical isomers are present as two independent molecules in the triclinic crystal system. The lipophilicity of the compounds was determined as the partition coefficient log K(ow) using the traditional shake-flask method. The in vitro inhibitory activity on acetylcholinesterase from electric eel and butyrylcholinesterase isolated from equine serum was determined. The inhibitory activity on acetylcholinesterase was significantly higher than that of the standard drug rivastigmine. The discussed compounds are also promising inhibitors of butyrylcholinesterase, as some of the prepared compounds inhibit butyrylcholinesterase better than the internal standards rivastigmine and galanthamine. The highest inhibitory activity (IC₅₀ = 1.66 μmol/L) corresponds to the compound 1-(4-isopropylphenyl)-3-[(R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethyl]imidazolidine-2,4,5-trione (3d). For all the studied compounds, the relationships between the lipophilicity and the chemical structure as well as their structure-activity relationships are discussed.
authors: Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 53210 Pardubice, Czech Republic.
authors: Vladimir
authors: V
authors: Pejchal
authors: Sarka
authors: S
authors: Stepankova
authors: Zdenka
authors: Z
authors: Padelkova
authors: Ales
authors: A
authors: Imramovsky
authors: Josef
authors: J
authors: Jampilek
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D057927:Hydrophobic and Hydrophilic Interactions; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D012016:Reference Values; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D002800:Cholinesterase Inhibitors; D048289:Imidazolidines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase