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.
- 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
The synthesis and chromatographic evaluation of a series of new Cinchona derived chiral weak anion exchangers is presented. Huisgen Cu(I) mediated alkyne-azide cycloaddition, so-called click chemistry, was used as an immobilization strategy. In this way it was possible to immobilize about 90% of offered selector via 1,2,3-triazole linker, which displays a more efficient way of binding the selector to modified silica compared to common radical mediated thiol-ene addition. Problems associated with potential radical scavenging properties of chiral selectors thereby could be circumvented. The evaluation of the synthesized chiral stationary phases regarding chromatographic behavior was carried out using polar organic mode mobile phase composition and a set of representative chiral organic acids. Different loading densities revealed an optimum selector density of about 310μmol/g chiral stationary phase with respect to resolution and selectivity. A decrease of performance was observed for higher loading, indicating mutual spatial influence of selector units leading to sterical hindrance. In addition, we observed that the effect of free azide groups on retention is negligible and the overall chromatographic behavior is comparable to other Cinchona derived chiral stationary phases.
- MeSH
- alkyny chemie MeSH
- aminokyseliny chemie MeSH
- azidy chemie MeSH
- chinidin analogy a deriváty chemická syntéza chemie MeSH
- chinin analogy a deriváty chemická syntéza chemie MeSH
- chromatografie MeSH
- cykloadiční reakce MeSH
- iontová výměna MeSH
- karbamáty chemická syntéza chemie MeSH
- oxid křemičitý MeSH
- stereoizomerie MeSH
- syntetická chemie okamžité shody MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- chinin analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- dna (nemoc) farmakoterapie terapie MeSH
- lidé MeSH
- methenamin aplikace a dávkování farmakologie terapeutické užití MeSH
- neopioidní analgetika aplikace a dávkování farmakologie terapeutické užití MeSH
- pyelitida farmakoterapie terapie MeSH
- tuberkulóza farmakoterapie terapie MeSH
- urologické nemoci farmakoterapie terapie MeSH
- železo terapeutické užití MeSH
- Check Tag
- lidé MeSH
