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

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.

New Tacrine Analogs as Acetylcholinesterase Inhibitors — Theoretical Study with Chemometric Analysis

“…The aim of this study was a pharmacokinetic characterization of a library of cholinesterase inhibitors for selection of the most appropriate compounds for in vivo tests, as well as the creation of a pharmacophore model that could be useful for the design of novel potential inhibitors. In this paper, we present a theoretical study of 32 new acetylcholinesterase inhibitors (Figure 1) for which in vitro analyses towards AChE, BuChE and their selectivities were previously reported [11,12,13,14,15,16]. Our analysis concerns the computer simulation of the ADMET process, which is very important in selecting specific compounds for subsequent experiments on animals.…”

Multifunctional properties of novel tacrine congeners: cholinesterase inhibition and cytotoxic activity

“…A novel series of novel 4‐fluoro‐ N ‐[ω‐(1,2,3,4‐tetrahydroacridin‐9‐ylamino)‐alkyl]‐benzamide derivatives, compounds 22a–h (Figure ), were prepared through a condensation reaction between 9‐aminoalkyl tetrahydroacridines and 4‐fluorobenzoic acid activated by 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (Szymański, Markowicz, & Mikiciuk‐Olasik, ; Szymański et al, ). Szymański et al used the same method to synthesize the novel 2,3‐dihydro‐1H‐cyclopenta[ b ]quinoline derivatives, which were synthesized through a condensation reaction between 9‐aminoquinolines 20a–h and activated 4‐fluorobenzoic acid (Szymański et al, ).…”

“…Synthesis of compounds 22a–h and quinoline‐fluoride compounds 23a–h (Szymański, Markowicz, Bajda, Malawska, & Mikiciuk‐Olasik, ; Szymański, Markowicz, Bajda, Malawska, & Mikiciuk‐Olasik, )…”

Synthesis of acridine cyclic imide hybrid molecules and their evaluation for anticancer activity

“…Acridine derivatives exhibiting antimalarial (Tomer et al, 2010;Guetzoyan et al, 2009), antimicrobial (Prabakaran et al, 2011), antibacterial (Daghigh et al, 2014) antiprion (Thi et al, 2008;Villa et al, 2011), anti-herpes (Goodell et al, 2006), antiviral , anticancer (Teitelbaum et al, 2012;Gardette et al, 2014;El-Deiry, 2008) activities are well documented in literature. Acridine derivatives also act as inhibitors of cholinesterase (Ip et al, 2008;Szymanski et al, 2012), telomerase (Hummersone et al, 2012) and human carbonic anhydrase isoenzymes (Yesildag et al, 2014).…”