Design, Synthesis and Evaluation of 8-(piperazin-1-yl)imidazo[1,2-a]pyrazine Derivatives as Acetylcholinesterase Inhibitors and Antioxidants
Abstract A series of 8-(piperazin-1-yl)imidazo[1,2-a]pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer's disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, 23l was the most potent AChE inhibitor with an IC50 value of 0.55 µM, which was higherthe IC50 value 5.01 of galantamine as the reference compound; while 23g had the best antioxidant activity with an IC50 value of 36.28 µM, which was lower than IC50 value of ascorbic acid as the control drug. Furthermore, the results of molecular docking studies indicate that 23l can simultaneously bind to both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction’s stability of 23l-AChE/BChE were also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 23l in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the molinspiration server, and the best active compound 23l matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, compound 23l as AChEIs is valuable for further development..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ResearchSquare.com - (2024) vom: 15. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wei, Ben-Ben [VerfasserIn] |
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| doi: |
10.21203/rs.3.rs-3688139/v1 |
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| PPN (Katalog-ID): |
XRA041888472 |
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| 245 | 1 | 0 | |a Design, Synthesis and Evaluation of 8-(piperazin-1-yl)imidazo[1,2-a]pyrazine Derivatives as Acetylcholinesterase Inhibitors and Antioxidants |
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| 520 | |a Abstract A series of 8-(piperazin-1-yl)imidazo[1,2-a]pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer's disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, 23l was the most potent AChE inhibitor with an IC50 value of 0.55 µM, which was higherthe IC50 value 5.01 of galantamine as the reference compound; while 23g had the best antioxidant activity with an IC50 value of 36.28 µM, which was lower than IC50 value of ascorbic acid as the control drug. Furthermore, the results of molecular docking studies indicate that 23l can simultaneously bind to both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction’s stability of 23l-AChE/BChE were also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 23l in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the molinspiration server, and the best active compound 23l matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, compound 23l as AChEIs is valuable for further development. | ||
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