Molecules 2011, 16(9), 7565-7582; doi:10.3390/molecules16097565
Article

1,3-Substituted Imidazolidine-2,4,5-triones: Synthesis and Inhibition of Cholinergic Enzymes

1 Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic 2 Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, Pardubice 53210, Czech Republic 3 Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic 4 Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1/3, 612 42 Brno, Czech Republic
* Authors to whom correspondence should be addressed.
Received: 16 August 2011; in revised form: 30 August 2011 / Accepted: 31 August 2011 / Published: 5 September 2011
(This article belongs to the Section Medicinal Chemistry)
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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 Kow 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.
Keywords: 1-(aryl)-3-[(R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethyl]imidazolidine-2,4,5-triones; X-ray diffraction; lipophilicity; in vitro acetylcholinesterase inhibition; in vitro butyrylcholinesterase inhibition; structure-activity relationships

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MDPI and ACS Style

Pejchal, V.; Stepankova, S.; Padelkova, Z.; Imramovsky, A.; Jampilek, J. 1,3-Substituted Imidazolidine-2,4,5-triones: Synthesis and Inhibition of Cholinergic Enzymes. Molecules 2011, 16, 7565-7582.

AMA Style

Pejchal V, Stepankova S, Padelkova Z, Imramovsky A, Jampilek J. 1,3-Substituted Imidazolidine-2,4,5-triones: Synthesis and Inhibition of Cholinergic Enzymes. Molecules. 2011; 16(9):7565-7582.

Chicago/Turabian Style

Pejchal, Vladimir; Stepankova, Sarka; Padelkova, Zdenka; Imramovsky, Ales; Jampilek, Josef. 2011. "1,3-Substituted Imidazolidine-2,4,5-triones: Synthesis and Inhibition of Cholinergic Enzymes." Molecules 16, no. 9: 7565-7582.

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