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; M. Markowicz; M. Bajda; B. Malawska; E. Mikiciuk-Olasik

doi:10.1055/s-0032-1329963

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2012; 62(12): 655-660
DOI: 10.1055/s-0032-1329963

Original Article

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

¹Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland

,

M. Markowicz

¹Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland

,

M. Bajda

²Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland

,

B. Malawska

²Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland

,

E. Mikiciuk-Olasik

¹Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland

› Author Affiliations

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.

Key words

Alzheimer’s disease - tacrine - fluorobenzoic acid - docking - Ellman’s method

Full Text

References

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