2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution

Abstract

In the present study we describe the synthesis and biological assessment of new tacrine analogs in the course of inhibition of acetylcholinesterase. The obtained molecules were synthesized in a condensation reaction between activated 6-BOC-hydrazinopyridine-3-carboxylic acid and 8-aminoalkyl derivatives of 2,3-dihydro-1H-cyclopenta[b]quinoline. Activities of the newly synthesized compounds were estimated by means of Ellman’s method. Compound 6h (IC50 = 3.65 nM) was found to be most active. All obtained novel compounds present comparable activity to that of tacrine towards acetylcholinesterase (AChE) and, simultaneously, lower activity towards butyrylcholinesterase (BChE). Apart from 6a, all synthesized compounds are characterized by a higher affinity for AChE and a lower affinity for BChE in comparison with tacrine. Among all obtained molecules, compound 6h presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling showed that all compounds demonstrated a similar binding mode with AChE and interacted with catalytic and peripheral sites of AChE. Also, a biodistribution study of compound 6a radiolabeled with 99mTc was performed.

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

“…However, it was more selective towards BChE (IC 50 = 0.0354 nM) over AChE [40]. Among the analogs 8 ( Figure 4, Table 1) reported as hybrids of tacrine and hydrazine nicotinate moiety by the same research group [41,42], the analog 8a was weaker eeAChE inhibitor (IC 50 = 308 nM) than the reference tacrine (IC 50 = 5.46 nM) and was selective towards esBChE (IC 50 = 0.65 nM) [41]. The other analog 8b, with longer alkyl spacer and smaller size of tricyclic ring compared to 8a, was stronger AChEI (IC 50 = 3.65 nM) than tacrine (IC 50 = 5.46 nM) with 4685 times selectivity towards AChE over BChE (IC 50 = 17100 nM) [42].…”

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

“…The final hydrochlorides, derivatives 19a–h , were obtained through crystallization from HCl in ether (Figure ). Quinoline compounds 21a–h were obtained by Szymański, Lázničková, Lázniček, et al () using the same method described above for tacrine analogs 19a–h (Figure ).…”

“…Synthesis of tacrine–hydrazinonicotinamide hybrids 19a–h , 8‐amino‐2,3‐dihydro‐1H‐cyclopenta[b]quinolones 20a–h and 6‐Hydrazino‐ N ‐[2‐(2,3‐dihydro‐1H‐cyclopenta[b] quinolin‐9‐ylamino)alkyl]nicotinamide hydrochlorides 21a–h (Szymański et al, ; Szymański, Markowicz, & Mikiciuk‐Olasik, ; Szymański, Lázničková, Lázniček, et al, )…”

Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells

“…Studies on biodistribution of tetrahydroacridine derivatives with similar structure showed that these compounds accumulate mainly in the rat's lungs and intestines [30]. A series of novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moieties were synthesized and evaluated for their anticancer properties by our research team previously [13,31].…”