Arzneimittelforschung 2012; 62(12): 655-660
DOI: 10.1055/s-0032-1329963
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Synthesis, Biological Activity and Molecular Modeling of 4-Fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide Derivatives as Cholinesterase Inhibitors

P. Szymański
Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
,
M. Markowicz
Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
,
M. Bajda
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
,
B. Malawska
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
,
E. Mikiciuk-Olasik
Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
› Author Affiliations
Further Information

Publication History

received 27 July 2012

accepted 21 October 2012

Publication Date:
15 November 2012 (eFirst)

Abstract

The aim of this study was to synthesize and determine the biological activity of new deri­vatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacri­dines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman’s spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation.