Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin-tacrine heterodimers via the carbamate bond. Compounds 14a-i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nM for acetylcholinesterase (AChE) and 0.24 nM for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4- to 256-fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.

It is already well documented that melatonin exhibits strong antioxidant properties. It traps several reactive oxygen species including singlet oxygen, peroxyl and hydroxyl radicals. Also, peroxynitrite-induced reactions are inhibited by melatonin. The oxidation of melatonin by singlet molecular oxygen [O(2) ((1)Delta(g))] may produce cyclic 3-hydroxymelatonin whose structure we have already studied. In this investigation we report on the synthesis of several melatonin analogues having a carbamate substituent instead of the methoxy group at 5 position of the indole ring. These compounds behave analogously to melatonin with respect to singlet oxygen and produce the corresponding cyclic 3-hydroxymelatonin analogues. The structures of the products were investigated with spectral methods and X-ray crystallography. The compounds obtained possess the 2,3,8,8a-tetrahydropyrrolo[2,3-b]indole heterocyclic system which is a structural motif characteristic of alkaloids, physostigmine and phenserine, that are potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors used in the Alzheimer's disease treatment. We measured the inhibitory activity of the obtained compounds against AChE and BChE from human erythrocytes and serum. In the case of the compounds having a phenylcarbamate and methoxyphenylcarbamate substituents, the inhibitory activity (IC(50)) ranged from 0.252 +/- 0.033 to 3.804 +/- 0.581 microM. Other compounds were less active and showed rather complex interactions with the structure-activity relationship in need of further investigation.

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The inhibition of cholinesterases plays a crucial role in a therapy of neurodegenerative diseases, including Alzheimer's disease. Especially, butyrylcholinesterase (BChE) has recently gained special interest. On the other hand, compounds having antioxidative properties may have a beneficial role in slowing down neurodegeneration processes. To combine these two effects, we synthesized a series of new derivatives of melatonin, which is a strong antioxidant, possessing structural elements essential for the inhibitory activity against cholinesterase. The structure of the new compounds was confirmed by NMR spectroscopy and mass spectrometry, and their activity against cholinesterases was measured in vitro using modified Ellman's method. The compounds obtained showed a high inhibitory activity, together with a strong selectivity against BChE. These results may point at new area of interest in a research on cholinesterase inhibitors.

Hybrid inhibitors of acetyl-and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin-donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase. K E Y W O R D S biological activity, drug design, hydrolases, medicinal chemistry, structure-activity relationship Arch Pharm Chem Life Sci. 2018;351:e1800194.wileyonlinelibrary.com/journal/ardp