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

International Journal of Molecular Sciences

Paweł Szymański¹  Alice Lázničková²  Milan Lázniპk²  Marek Bajda³  Barbara Malawska³  Magdalena Markowicz¹ 

[1] Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, ul. Muszyńskiego 1, Lodz 90-151, Poland; E-Mails:;Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove CZ-50005, Czech Republic; E-Mails:;Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland; E-Mails:

关键词: biological activity;    medicinal chemistry;    isotopic labeling;    drug design;    radiopharmaceuticals;   

DOI  :  10.3390/ijms130810067

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.