Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors
Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen <i>N</i>-methyl-piperazine chalcones were synthesized,...
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MDPI AG
2023-01-01
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| Online Access: | https://www.mdpi.com/1424-8247/16/1/83 |
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| author | Ashraf K. El-Damasy Jong Eun Park Hyun Ji Kim Jinhyuk Lee Eun-Kyoung Bang Hoon Kim Gyochang Keum |
| author_facet | Ashraf K. El-Damasy Jong Eun Park Hyun Ji Kim Jinhyuk Lee Eun-Kyoung Bang Hoon Kim Gyochang Keum |
| author_sort | Ashraf K. El-Damasy |
| collection | DOAJ |
| description | Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen <i>N</i>-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound <b>2k</b> (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC<sub>50</sub> of 0.71 μM and selectivity index (SI) of 56.34, followed by <b>2n</b> (2-fluoro-5-bromophenyl derivative) (IC<sub>50</sub> = 1.11 μM, SI = 16.04). Compounds <b>2k</b> and <b>2n</b> were reversible competitive MAO-B inhibitors with K<sub>i</sub> values of 0.21 and 0.28 μM, respectively. Moreover, <b>2k</b> and <b>2n</b> effectively inhibited AChE with IC<sub>50</sub> of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound <b>2o</b> elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC<sub>50</sub> of 1.19–3.87 μM. A cell-based assay of compounds <b>2k</b> and <b>2n</b> against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, <b>2k</b> showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that <b>2k</b> and <b>2n</b> are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds <b>2k</b> and <b>2n</b> could serve as promising potential candidates for the treatment of neurodegenerative diseases. |
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| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
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| publishDate | 2023-01-01 |
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| spelling | doaj.art-32a44b2c4bc94d6885f380f1e6a4b63b2023-11-30T23:55:34ZengMDPI AGPharmaceuticals1424-82472023-01-011618310.3390/ph16010083Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE InhibitorsAshraf K. El-Damasy0Jong Eun Park1Hyun Ji Kim2Jinhyuk Lee3Eun-Kyoung Bang4Hoon Kim5Gyochang Keum6Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of KoreaDepartment of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of KoreaCenter for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of KoreaDisease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of KoreaCenter for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of KoreaDepartment of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of KoreaCenter for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of KoreaMonoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen <i>N</i>-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound <b>2k</b> (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC<sub>50</sub> of 0.71 μM and selectivity index (SI) of 56.34, followed by <b>2n</b> (2-fluoro-5-bromophenyl derivative) (IC<sub>50</sub> = 1.11 μM, SI = 16.04). Compounds <b>2k</b> and <b>2n</b> were reversible competitive MAO-B inhibitors with K<sub>i</sub> values of 0.21 and 0.28 μM, respectively. Moreover, <b>2k</b> and <b>2n</b> effectively inhibited AChE with IC<sub>50</sub> of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound <b>2o</b> elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC<sub>50</sub> of 1.19–3.87 μM. A cell-based assay of compounds <b>2k</b> and <b>2n</b> against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, <b>2k</b> showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that <b>2k</b> and <b>2n</b> are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds <b>2k</b> and <b>2n</b> could serve as promising potential candidates for the treatment of neurodegenerative diseases.https://www.mdpi.com/1424-8247/16/1/83<i>N</i>-methyl-piperazine chalconesmonoamine oxidasecholinesterasekinetic studydocking simulation |
| spellingShingle | Ashraf K. El-Damasy Jong Eun Park Hyun Ji Kim Jinhyuk Lee Eun-Kyoung Bang Hoon Kim Gyochang Keum Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors Pharmaceuticals <i>N</i>-methyl-piperazine chalcones monoamine oxidase cholinesterase kinetic study docking simulation |
| title | Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors |
| title_full | Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors |
| title_fullStr | Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors |
| title_full_unstemmed | Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors |
| title_short | Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors |
| title_sort | identification of new i n i methyl piperazine chalcones as dual mao b ache inhibitors |
| topic | <i>N</i>-methyl-piperazine chalcones monoamine oxidase cholinesterase kinetic study docking simulation |
| url | https://www.mdpi.com/1424-8247/16/1/83 |
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