Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.
- Klíčová slova
- 15-lipoxygenase, Acetylcholinesterase, Alzheimer's disease, Butyrylcholinesterase, Cyclooxygenase-2,
- MeSH
- acetylcholin nedostatek MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- buněčné linie MeSH
- buňky PC12 MeSH
- cholinesterasové inhibitory chemie MeSH
- inhibitory cyklooxygenasy 2 chemie MeSH
- inhibitory lipoxygenas chemie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- neurony účinky léků enzymologie patologie MeSH
- racionální návrh léčiv MeSH
- semikarbazidy chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- triazoly chemie farmakologie MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholin MeSH
- cholinesterasové inhibitory MeSH
- inhibitory cyklooxygenasy 2 MeSH
- inhibitory lipoxygenas MeSH
- semikarbazidy MeSH
- thiosemicarbazide MeSH Prohlížeč
- triazoly MeSH
We investigated the functional characteristics of pre- and postsynaptic cholinergic transmission in APPswe/PS1dE9 double transgenic mice at a young age (7-10 weeks) before the onset of amyloid plaque formation and at adult age (5-6 months) at its onset. We compared brain slices from cerebral cortex and hippocampus with amyloid deposits to slices from striatum with no amyloid plaques by 6 months of age. In young transgenic mice we found no impairments of preformed and newly synthesized [(3)H]-ACh release, indicating intact releasing machinery and release turnover, respectively. Adult transgenic mice displayed a significant increase in preformed [(3)H]-ACh release in cortex but a decrease in hippocampus and striatum. The extent of presynaptic muscarinic autoregulation was unchanged. Evoked release of newly synthesized [(3)H]-ACh was significantly reduced in the cortex and hippocampus but unchanged in the striatum. Carbachol-induced G-protein activation in cortical membranes displayed decreased potency but normal efficacy in adult animals and no changes in young animals. These results indicate that functional pre- and postsynaptic cholinergic deficits are not present in APPswe/PS1dE9 transgenic mice before 10 weeks of age, but develop along with beta-amyloid accumulation in the brain.
- MeSH
- acetylcholin nedostatek MeSH
- Alzheimerova nemoc genetika metabolismus patofyziologie MeSH
- amyloid metabolismus MeSH
- amyloidový prekurzorový protein beta genetika MeSH
- cholinergní agonisté farmakologie MeSH
- cholinergní vlákna metabolismus patologie MeSH
- degenerace nervu metabolismus patologie MeSH
- down regulace genetika MeSH
- hipokampus metabolismus patologie patofyziologie MeSH
- modely nemocí na zvířatech MeSH
- mozek - chemie genetika MeSH
- mozek růst a vývoj metabolismus patofyziologie MeSH
- mozková kůra růst a vývoj metabolismus patofyziologie MeSH
- myši transgenní MeSH
- myši MeSH
- orgánové kultury - kultivační techniky MeSH
- presenilin-1 genetika MeSH
- proteiny vázající GTP účinky léků genetika metabolismus MeSH
- receptory muskarinové metabolismus MeSH
- stárnutí metabolismus MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholin MeSH
- amyloid MeSH
- amyloidový prekurzorový protein beta MeSH
- cholinergní agonisté MeSH
- presenilin-1 MeSH
- proteiny vázající GTP MeSH
- receptory muskarinové MeSH
