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Article

Quinuclidine-Based Carbamates as Potential CNS Active Compounds

1
Institute for Medical Research and Occupational Health, Ksaverska Cesta 2, HR-10 000 Zagreb, Croatia
2
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
Academic Editor: Robert Vianello
Pharmaceutics 2021, 13(3), 420; https://doi.org/10.3390/pharmaceutics13030420
Received: 26 February 2021 / Revised: 15 March 2021 / Accepted: 17 March 2021 / Published: 20 March 2021
(This article belongs to the Special Issue Covalent Inhibitors as Selective Drug Candidates)
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 103 M−1 min−1 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. View Full-Text
Keywords: Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; inhibition; covalent binding; cytotoxicity Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; inhibition; covalent binding; cytotoxicity
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MDPI and ACS Style

Matošević, A.; Radman Kastelic, A.; Mikelić, A.; Zandona, A.; Katalinić, M.; Primožič, I.; Bosak, A.; Hrenar, T. Quinuclidine-Based Carbamates as Potential CNS Active Compounds. Pharmaceutics 2021, 13, 420. https://doi.org/10.3390/pharmaceutics13030420

AMA Style

Matošević A, Radman Kastelic A, Mikelić A, Zandona A, Katalinić M, Primožič I, Bosak A, Hrenar T. Quinuclidine-Based Carbamates as Potential CNS Active Compounds. Pharmaceutics. 2021; 13(3):420. https://doi.org/10.3390/pharmaceutics13030420

Chicago/Turabian Style

Matošević, Ana, Andreja Radman Kastelic, Ana Mikelić, Antonio Zandona, Maja Katalinić, Ines Primožič, Anita Bosak, and Tomica Hrenar. 2021. "Quinuclidine-Based Carbamates as Potential CNS Active Compounds" Pharmaceutics 13, no. 3: 420. https://doi.org/10.3390/pharmaceutics13030420

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