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. 2021 Mar 20;13(3):420.
doi: 10.3390/pharmaceutics13030420.

Quinuclidine-Based Carbamates as Potential CNS Active Compounds

Ana Matošević  1 , Andreja Radman Kastelic  2 , Ana Mikelić  2 , Antonio Zandona  1 , Maja Katalinić  1 , Ines Primožič  2 , Anita Bosak  1 , Tomica Hrenar  2
Affiliations

Quinuclidine-Based Carbamates as Potential CNS Active Compounds

Ana Matošević et al. Pharmaceutics. .

Abstract

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.

Keywords: Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; covalent binding; cytotoxicity; inhibition.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The structures of currently approved carbamate drugs for treatment of neurodegenerative disorders.
Figure 2
Figure 2
The structure of the synthesized compounds.
Scheme 1
Scheme 1
Progressive inhibition of cholinesterases by carbamates.
Figure 3
Figure 3
Representative experiment of the inhibition of butyrylcholinesterase (BChE) by compound 8. Panel (A): points indicate the logarithm of residual activity, while the slope of the lines determines the first-order rate constant kobs. Panel (B): The constants kobs were plotted as a function of carbamate concentration wherefrom the second-order rate constant, ki, was calculated.
Figure 4
Figure 4
Screen plot for principal component analysis PCA of the compound energy fingerprints collected during molecular dynamics simulations.
Figure 5
Figure 5
Multivariate regression models of dissociation constant of compounds for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
Figure 6
Figure 6
Radar plot of physicochemical properties (molecular weight, MW; lipophilicity coefficient, logP; number of hydrogen bonds donors, HBD, and acceptors HBA; rotatable bonds, RB; polar surface area, PSA) of the tested carbamates. The recommended values for the CNS-active drugs are presented by a dashed red line [56,57].
Figure 7
Figure 7
Cytotoxicity of tested carbamates in concentrations 6.25–400 μM on A549, HEK293 and SH-SY5Y cells. Data are given as a mean ± SE (n = 6) of two independent experiments.
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