Design, docking, synthesis and biological evaluation of chromone derivatives as dual inhibitors of Interleukin‐6 and acetylcholinesterase for treatment of Alzheimer’s Disease
Abstract Background Interleukin‐6 (IL‐6) and acetylcholinesterase (AChE) are two important targets implicated in the progression of Alzheimer’s Disease (AD). Concurrent inhibition of both IL‐6 and AChE by a molecule presents an effective strategy for the treatment of AD. In the present study, novel molecules are designed by coupling a chromone and a N,N‐disubstituted carbamoyl amine as pharmacophore for IL‐6 and AChE inhibition, respectively. Method Four series ( S1‐ S4) of 40 compounds are designed by coupling the two selected pharmacophore through alkyl linkers of different lengths (1‐4 carbon atoms). All designed compounds are docked in AChE (PDB 1EVE). The compounds having docking score ±20% of donepezil (the lead molecule) are synthesised, and evaluated for AChE inhibitory activity. The compounds showing >45% inhibition of AChE are further evaluated for IL‐6 inhibitory activity. Result Twelve best‐fit compounds (AChE docking score >8.3) among all designed compounds are selected for synthesis. The data suggests that a 1‐ or 2‐carbon atom(s) linker is conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier with good oral bioavailability. These compounds are synthesised and evaluated for anti‐AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL‐6 inhibitory activity. Compound S1f is found to be the most potent inhibitor of both AChE and IL‐6 (IC500.7 and 0.8 µM, respectively). Conclusion A chromone moiety connected to a piperidine ring through a 1‐carbon atom linker may prove as a useful template for the development of new chemical entities effective against AD..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Alzheimer's & Dementia - 19(2023) |
| Beteiligte Personen: |
Kaur, Sukhvir [VerfasserIn] |
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| Anmerkungen: |
© 2023 the Alzheimer's Association. |
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| Umfang: |
1 |
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| doi: |
10.1002/alz.066745 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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WLY014960842 |
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| 245 | 1 | 0 | |a Design, docking, synthesis and biological evaluation of chromone derivatives as dual inhibitors of Interleukin‐6 and acetylcholinesterase for treatment of Alzheimer’s Disease |
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| 520 | |a Abstract Background Interleukin‐6 (IL‐6) and acetylcholinesterase (AChE) are two important targets implicated in the progression of Alzheimer’s Disease (AD). Concurrent inhibition of both IL‐6 and AChE by a molecule presents an effective strategy for the treatment of AD. In the present study, novel molecules are designed by coupling a chromone and a N,N‐disubstituted carbamoyl amine as pharmacophore for IL‐6 and AChE inhibition, respectively. Method Four series ( S1‐ S4) of 40 compounds are designed by coupling the two selected pharmacophore through alkyl linkers of different lengths (1‐4 carbon atoms). All designed compounds are docked in AChE (PDB 1EVE). The compounds having docking score ±20% of donepezil (the lead molecule) are synthesised, and evaluated for AChE inhibitory activity. The compounds showing >45% inhibition of AChE are further evaluated for IL‐6 inhibitory activity. Result Twelve best‐fit compounds (AChE docking score >8.3) among all designed compounds are selected for synthesis. The data suggests that a 1‐ or 2‐carbon atom(s) linker is conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier with good oral bioavailability. These compounds are synthesised and evaluated for anti‐AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL‐6 inhibitory activity. Compound S1f is found to be the most potent inhibitor of both AChE and IL‐6 (IC500.7 and 0.8 µM, respectively). Conclusion A chromone moiety connected to a piperidine ring through a 1‐carbon atom linker may prove as a useful template for the development of new chemical entities effective against AD. | ||
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