In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.

• Klíčová slova
• Alzheimer disease, kojic acid, multitarget small molecules, tacrine,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv MeSH
• takrin chemická syntéza   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
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• neuroprotektivní látky MeSH
• takrin MeSH

The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g. neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients' quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs.

• Klíčová slova
• chelating agents, drug development, metallodrugs,
• MeSH
• amyloid chemie   metabolismus   MeSH
• amyloidní beta-protein chemie   metabolismus   MeSH
• chelátory chemie   farmakologie   terapeutické užití   MeSH
• kovy chemie   metabolismus   MeSH
• lidé MeSH
• neurodegenerativní nemoci farmakoterapie   etiologie   metabolismus   patologie   MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vyvíjení léků * MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• amyloid MeSH
• amyloidní beta-protein MeSH
• chelátory MeSH
• kovy MeSH

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

• Klíčová slova
• Acetylcholinesterase, Alzheimer’s disease, donepezil, multi-target directed ligands, oxidative stress,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• antioxidancia chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• donepezil MeSH
• indany chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• piperidiny chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antioxidancia MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• indany MeSH
• piperidiny MeSH

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

• Klíčová slova
• Alzheimer’s disease, antioxidants, cholinesterase inhibitors, hepatotoxicity, multicomponent reactions, multitarget-directed ligands, quinazolinones,
• MeSH
• Alzheimerova nemoc prevence a kontrola   MeSH
• antioxidancia chemická syntéza   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• játra účinky léků   MeSH
• lidé MeSH
• spektrální analýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• cholinesterasové inhibitory 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

Cholinesterase activity in blood of laboratory rats was monitored. Rats were intoxicated with paraoxon at dosis of 0 - 65 - 125 - 170 - 250 - 500 nmol. The 250 nmol dose was found to be the LD(50). An electrochemical sensor was found useful to provide information about cholinesterase activity. The decrease of cholinesterase activity was correlated to intoxication symptoms and mortality level. It was found that the symptoms of intoxication are not observed while at least 50% of cholinesterase activity in blood remains. The minimal cholinesterase activity essential to survival is around 10%, when compared with the initial state. No changes in levels of low moleculary weight antioxidants were observed.

• Klíčová slova
• acetylcholinesterase, activity, blood, butyrylcholinesterase, cholinesterase, intoxication, paraoxon, pesticide,
• Publikační typ
• časopisecké články MeSH