Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells
Abstract Background The loss of cholinergic neurotransmission in Alzheimer's disease (AD) patients' brain is accompanied by a reduced concentration of Acetylcholine (ACh) within synaptic clefts. Thus, the use of acetylcholinesterase inhibitors (AChEIs) to block the cholinergic degradation...
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| Format: | Article |
| Language: | English |
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BMC
2022-02-01
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| Series: | BMC Chemistry |
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| Online Access: | https://doi.org/10.1186/s13065-022-00799-w |
| _version_ | 1818501050445856768 |
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| author | Maryam Taheri Samira Aslani Hossein Ghafouri Asadollah Mohammadi Vaha Akbary Moghaddam Nastarn Moradi Hananeh Naeimi |
| author_facet | Maryam Taheri Samira Aslani Hossein Ghafouri Asadollah Mohammadi Vaha Akbary Moghaddam Nastarn Moradi Hananeh Naeimi |
| author_sort | Maryam Taheri |
| collection | DOAJ |
| description | Abstract Background The loss of cholinergic neurotransmission in Alzheimer's disease (AD) patients' brain is accompanied by a reduced concentration of Acetylcholine (ACh) within synaptic clefts. Thus, the use of acetylcholinesterase inhibitors (AChEIs) to block the cholinergic degradation of ACh is a promising approach for AD treatment. In the present study, a series of 2-chloro-3-hydrazinopyrazine derivatives (CHP1-5) were designed, synthesized, and biologically evaluated as potential multifunctional anti-AD agents. Methods In addition, the chemical structures and purity of the synthesized compounds were elucidated through using IR, 1H and 13C NMR, and elemental analyses. Further, the intended compounds were assessed in vitro for their AChE inhibitory and neuroprotective effects. Furthermore, DPPH, FRAP and ABTS assays were utilized to determine their antioxidant activity. The statistical analysis was performed using one-way ANOVA. Results Based on the results, CHP4 and CHP5 exhibited strong AChE inhibitory effects with the IC50 values of 3.76 and 4.2 µM compared to the donepezil (0.53 µM), respectively. The study examined the effect and molecular mechanism of CHP4 on the Ab1–42-induced cytotoxicity in differentiated PC12 cells. At concentrations of 0–100 μM, CHP4 was non-toxic in PC12. Additionally, Ab1–42 significantly stimulated tau hyperphosphorylation and induced differentiated PC12 cell death. Further, CHP4 resulted in diminishing the Ab1–42-induced toxicity in PC12 cell significantly. CHP4 at 30 μM concentration significantly increased the Ab1–42-induced HSP70 expression and decreased tau hyperphosphorylation. Conclusions According to the results of our studies CHP4 can be considered as safe and efficient AChEI and employed as a potential multifunctional anti-AD agent. |
| first_indexed | 2024-12-10T20:50:55Z |
| format | Article |
| id | doaj.art-364fc1e64e974da98ac03759a9809a26 |
| institution | Directory Open Access Journal |
| issn | 2661-801X |
| language | English |
| last_indexed | 2024-12-10T20:50:55Z |
| publishDate | 2022-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Chemistry |
| spelling | doaj.art-364fc1e64e974da98ac03759a9809a262022-12-22T01:34:05ZengBMCBMC Chemistry2661-801X2022-02-0116111210.1186/s13065-022-00799-wSynthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cellsMaryam Taheri0Samira Aslani1Hossein Ghafouri2Asadollah Mohammadi3Vaha Akbary Moghaddam4Nastarn Moradi5Hananeh Naeimi6Department of Biology, Faculty of Basic Sciences, University of GuilanDepartment of Biology, Faculty of Basic Sciences, University of GuilanDepartment of Biology, Faculty of Basic Sciences, University of GuilanDepartment of Chemistry, Faculty of Sciences, University of GuilanDepartment of Biology, Faculty of Basic Sciences, University of GuilanDepartment of Biology, Faculty of Basic Sciences, University of GuilanDepartment of Biology, Faculty of Basic Sciences, University of GuilanAbstract Background The loss of cholinergic neurotransmission in Alzheimer's disease (AD) patients' brain is accompanied by a reduced concentration of Acetylcholine (ACh) within synaptic clefts. Thus, the use of acetylcholinesterase inhibitors (AChEIs) to block the cholinergic degradation of ACh is a promising approach for AD treatment. In the present study, a series of 2-chloro-3-hydrazinopyrazine derivatives (CHP1-5) were designed, synthesized, and biologically evaluated as potential multifunctional anti-AD agents. Methods In addition, the chemical structures and purity of the synthesized compounds were elucidated through using IR, 1H and 13C NMR, and elemental analyses. Further, the intended compounds were assessed in vitro for their AChE inhibitory and neuroprotective effects. Furthermore, DPPH, FRAP and ABTS assays were utilized to determine their antioxidant activity. The statistical analysis was performed using one-way ANOVA. Results Based on the results, CHP4 and CHP5 exhibited strong AChE inhibitory effects with the IC50 values of 3.76 and 4.2 µM compared to the donepezil (0.53 µM), respectively. The study examined the effect and molecular mechanism of CHP4 on the Ab1–42-induced cytotoxicity in differentiated PC12 cells. At concentrations of 0–100 μM, CHP4 was non-toxic in PC12. Additionally, Ab1–42 significantly stimulated tau hyperphosphorylation and induced differentiated PC12 cell death. Further, CHP4 resulted in diminishing the Ab1–42-induced toxicity in PC12 cell significantly. CHP4 at 30 μM concentration significantly increased the Ab1–42-induced HSP70 expression and decreased tau hyperphosphorylation. Conclusions According to the results of our studies CHP4 can be considered as safe and efficient AChEI and employed as a potential multifunctional anti-AD agent.https://doi.org/10.1186/s13065-022-00799-wAcetylcholinesterase inhibitorsAlzheimer's disease2-Chloro-3-hydrazinopyrazinePC12 cells |
| spellingShingle | Maryam Taheri Samira Aslani Hossein Ghafouri Asadollah Mohammadi Vaha Akbary Moghaddam Nastarn Moradi Hananeh Naeimi Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells BMC Chemistry Acetylcholinesterase inhibitors Alzheimer's disease 2-Chloro-3-hydrazinopyrazine PC12 cells |
| title | Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells |
| title_full | Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells |
| title_fullStr | Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells |
| title_full_unstemmed | Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells |
| title_short | Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells |
| title_sort | synthesis in vitro biological evaluation and molecular modelling of new 2 chloro 3 hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on pc12 cells |
| topic | Acetylcholinesterase inhibitors Alzheimer's disease 2-Chloro-3-hydrazinopyrazine PC12 cells |
| url | https://doi.org/10.1186/s13065-022-00799-w |
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