Quinuclidine-Based Carbamates as Potential CNS Active Compounds
The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using qui...
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MDPI AG
2021-03-01
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| Online Access: | https://www.mdpi.com/1999-4923/13/3/420 |
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| author | Ana Matošević Andreja Radman Kastelic Ana Mikelić Antonio Zandona Maja Katalinić Ines Primožič Anita Bosak Tomica Hrenar |
| author_facet | Ana Matošević Andreja Radman Kastelic Ana Mikelić Antonio Zandona Maja Katalinić Ines Primožič Anita Bosak Tomica Hrenar |
| author_sort | Ana Matošević |
| collection | DOAJ |
| description | The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule. All of the prepared carbamates displayed a time-dependent inhibition with overall inhibition rate constants in the 10<sup>3</sup> M<sup>−1</sup> min<sup>−1</sup> range. None of the compounds showed pronounced selectivity for any of the cholinesterases. The in silico determined ability of compounds to cross the blood–brain barrier (BBB) revealed that six compounds should be able to pass the BBB by passive transport. In addition, the compounds did not show toxicity toward cells that represented the main models of individual organs. By machine learning, the most optimal regression models for the prediction of bioactivity were established and validated. Models for AChE and BChE described 89 and 90% of the total variations among the data, respectively. These models facilitated the prediction and design of new and more potent inhibitors. Altogether, our study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer’s disease treatment. |
| first_indexed | 2024-03-10T13:04:03Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T13:04:03Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-a3342646a5eb4a7dbcbfc8787df0e4be2023-11-21T11:19:26ZengMDPI AGPharmaceutics1999-49232021-03-0113342010.3390/pharmaceutics13030420Quinuclidine-Based Carbamates as Potential CNS Active CompoundsAna Matošević0Andreja Radman Kastelic1Ana Mikelić2Antonio Zandona3Maja Katalinić4Ines Primožič5Anita Bosak6Tomica Hrenar7Institute for Medical Research and Occupational Health, Ksaverska Cesta 2, HR-10 000 Zagreb, CroatiaDepartment of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, CroatiaDepartment of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, CroatiaInstitute for Medical Research and Occupational Health, Ksaverska Cesta 2, HR-10 000 Zagreb, CroatiaInstitute for Medical Research and Occupational Health, Ksaverska Cesta 2, HR-10 000 Zagreb, CroatiaDepartment of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, CroatiaInstitute for Medical Research and Occupational Health, Ksaverska Cesta 2, HR-10 000 Zagreb, CroatiaDepartment of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, CroatiaThe treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule. All of the prepared carbamates displayed a time-dependent inhibition with overall inhibition rate constants in the 10<sup>3</sup> M<sup>−1</sup> min<sup>−1</sup> range. None of the compounds showed pronounced selectivity for any of the cholinesterases. The in silico determined ability of compounds to cross the blood–brain barrier (BBB) revealed that six compounds should be able to pass the BBB by passive transport. In addition, the compounds did not show toxicity toward cells that represented the main models of individual organs. By machine learning, the most optimal regression models for the prediction of bioactivity were established and validated. Models for AChE and BChE described 89 and 90% of the total variations among the data, respectively. These models facilitated the prediction and design of new and more potent inhibitors. Altogether, our study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer’s disease treatment.https://www.mdpi.com/1999-4923/13/3/420Alzheimer’s diseaseacetylcholinesterasebutyrylcholinesteraseinhibitioncovalent bindingcytotoxicity |
| spellingShingle | Ana Matošević Andreja Radman Kastelic Ana Mikelić Antonio Zandona Maja Katalinić Ines Primožič Anita Bosak Tomica Hrenar Quinuclidine-Based Carbamates as Potential CNS Active Compounds Pharmaceutics Alzheimer’s disease acetylcholinesterase butyrylcholinesterase inhibition covalent binding cytotoxicity |
| title | Quinuclidine-Based Carbamates as Potential CNS Active Compounds |
| title_full | Quinuclidine-Based Carbamates as Potential CNS Active Compounds |
| title_fullStr | Quinuclidine-Based Carbamates as Potential CNS Active Compounds |
| title_full_unstemmed | Quinuclidine-Based Carbamates as Potential CNS Active Compounds |
| title_short | Quinuclidine-Based Carbamates as Potential CNS Active Compounds |
| title_sort | quinuclidine based carbamates as potential cns active compounds |
| topic | Alzheimer’s disease acetylcholinesterase butyrylcholinesterase inhibition covalent binding cytotoxicity |
| url | https://www.mdpi.com/1999-4923/13/3/420 |
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