Selective inhibition of butyrylcholinesterase by singlet oxygen-generated melatonin derivatives

Abstract

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.

Highly selective inhibition of butyrylcholinesterase by a novel melatonin–tacrine heterodimers

“…The novel melatonin–tacrine heterodimers 14a‐i are potent inhibitors of both AChE and BuChE, with IC 50 values in the low nanomolar range in most cases better than tacrine 4 and compounds previously obtained by us . They inhibited BuChE with IC 50 = 0.24–58.17 n m , exhibiting an interesting selectivity, being from 4‐ to 256‐fold more active toward BuChE than AChE.…”

“…In our previous publications , we reported several carbamate derivatives of melatonin and carbamate derivatives which contained the product of melatonin oxidation by singlet oxygen. The in vitro tests showed high biological activity of these derivatives.…”

Isoprenoid Alcohols are Susceptible to Oxidation with Singlet Oxygen and Hydroxyl Radicals

“…In the second line of experiments, singlet oxygen was generated during irradiation of the reaction mixture with UV light in the presence of porphyrin as a photosensitizer (‘light’ conditions) [ 24 ].…”

“…The reaction was performed as described earlier for carbamate derivative [ 24 ] with modifications. Briefly, 100 mg (143 µmol) of P-10 or 0.9 g (5.69 mmol) of Prenol-2 was dissolved in 75 ml of the mixture of solvents (2-propanol/ethanol/dichloromethane 1:1:4, by vol or methanol/dichloromethane 1:2, by vol, for P-10 and P-2, respectively) supplemented with 300 µl of pyridine.…”