Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase
| Autor: | Salwa Elkazaz, Ehab D. AlFadly, Ignacio Moraleda, Manuela Bartolini, Marwa M. Abu-Serie, Hossam A. Shaltout, Ahmed S.F. Belal, Firas Kobeissy, Manal N. S. Saudi, Nour-Mounira Z. Bakkar, Anna Tramarin, Perihan A. Elzahhar, Ondrej Soukup, Isabel Iriepa, Jana Janockova, Rim W. Rafeh, Doaa A. Ghareeb, Ahmed F. El-Yazbi |
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| Přispěvatelé: | AlFadly E.D., Elzahhar P.A., Tramarin A., Elkazaz S., Shaltout H., Abu-Serie M.M., Janockova J., Soukup O., Ghareeb D.A., El-Yazbi A.F., Rafeh R.W., Bakkar N.-M.Z., Kobeissy F., Iriepa I., Moraleda I., Saudi M.N.S., Bartolini M., Belal A.S.F. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
01 natural sciences PC12 Cells chemistry.chemical_compound Mice 15-lipoxygenase Drug Discovery Cholinesterase Inhibitor Lipoxygenase Inhibitors Cyclooxygenase-2 Butyrylcholinesterase Neurons 0303 health sciences biology General Medicine Alzheimer's disease Ligand (biochemistry) Acetylcholinesterase Semicarbazides Molecular Docking Simulation Tacrine medicine.drug Human Cyclooxygenase 2 Inhibitor Lipoxygenase Inhibitor Cell Line 03 medical and health sciences Alzheimer Disease medicine Animals Humans 030304 developmental biology Cholinesterase Inflammation Ligand efficiency Cyclooxygenase 2 Inhibitors 010405 organic chemistry Animal Semicarbazide Organic Chemistry Zileuton Neuron Triazoles Acetylcholine PC12 Cell 0104 chemical sciences Rats chemistry Drug Design biology.protein Cholinergic Rat Cholinesterase Inhibitors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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