title: 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 (IC(50) = 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 (99m)Tc was performed.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, ul. Muszyńskiego 1, Lodz 90-151, Poland.
authors.forename: Paweł
authors.identifier: 0000-0003-3438-7509
authors.initials: P
authors.lastname: Szymański
authors.affiliation: Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove CZ-50005, Czech Republic.
authors.forename: Alice
authors.initials: A
authors.lastname: Lázničková
authors.affiliation: Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove CZ-50005, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Lázniček
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, ul. Muszyńskiego 1, Lodz 90-151, Poland.
authors.forename: Magdalena
authors.identifier: 0000-0002-1012-6550
authors.initials: M
authors.lastname: Markowicz
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, ul. Muszyńskiego 1, Lodz 90-151, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Mikiciuk-Olasik
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling; D008958:Models, Molecular; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C000601073:6-hydrazino-N-(9-(2,3-dihydro-1H-cyclopenta(b)quinolin-9-ylamino)nonyl)nicotinamide hydrochloride; D002800:Cholinesterase Inhibitors; D011804:Quinolines; D009536:Niacinamide; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase