Tacrine was the first drug to be approved for Alzheimer's disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.

• Klíčová slova
• 6-chlorotacrine, 7-methoxytacrine, Alzheimer’s disease, bis(7)-tacrine, cholinesterases, in silico, in vitro, squaramides, tacrine,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• chinin analogy a deriváty   chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• takrin chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• chinin MeSH
• cholinesterasové inhibitory MeSH
• squaramide MeSH Prohlížeč
• takrin MeSH

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.

• Klíčová slova
• biological activity, drug design, isotopic labeling, medicinal chemistry, radiopharmaceuticals,
• MeSH
• acetylcholinesterasa chemie   MeSH
• butyrylcholinesterasa chemie   MeSH
• chinoliny chemická syntéza   farmakokinetika   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakokinetika   MeSH
• izotopové značení MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• niacinamid analogy a deriváty   chemická syntéza   farmakokinetika   MeSH
• takrin farmakologie   MeSH
• tkáňová distribuce MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 6-hydrazino-N-(9-(2,3-dihydro-1H-cyclopenta(b)quinolin-9-ylamino)nonyl)nicotinamide hydrochloride MeSH Prohlížeč
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• chinoliny MeSH
• cholinesterasové inhibitory MeSH
• niacinamid MeSH
• takrin MeSH