The oxidation products of melatonin derivatives exhibit acetylcholinesterase and butyrylcholinesterase inhibitory activity

Abstract

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.

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

“…The function of cholinesterase inhibitors (ChEIs) is to increase the endogenous levels of acetylcholine (ACh) in the brains of AD patients, eventually increasing cholinergic neurotransmission. It is not surprising that ChEIs have shown better results in the treatment of AD than any other strategy explored; for example, compounds having a 2,3,8,8a-tetrahydropyrrolo[2,3-b]indole heterocyclic system, a characteristic structural motif of alkaloids such as physostigmine and phenserine, are considered potent ChEIs for use in AD treatment [11]. Both ChEs show a characteristic cleft intruding into the enzyme surface, containing the catalytic triad and choline binding sites where ACh is cleaved.…”

Melatonin Metabolism in the Central Nervous System

“…On this basis, several derivatives of c3OHM have been synthesized and investigated for inhibition of acetyland butyrylcholinesterase activities [127]. This might be of value with regard to the assumed possibility of interfering with the progression of Alzheimer's disease by inhibiting the acylcholinesterases.…”

Selective inhibition of butyrylcholinesterase by singlet oxygen-generated melatonin derivatives

“…The original N ‐acetylserotonin 5 was obtained by the acetylation of serotonin, according to the procedure described in our previous work [12]. Coupling of compound 5 with ethyl isocyanate, in the presence of catalytic amount of sodium, afforded a carbamate derivative 6 in 57% yield.…”

“…We have already described the synthesis of compound 9 [12] but we found that the singlet oxygen–induced cyclization gave better results when tetraphenyl porphyrin was used as a photosensitizer. Mild methanolysis in the presence of sodium methoxide, followed by the removal of the silyl protecting group, gave a stable compound 10 , which may serve as a substrate for various O ‐acylations at the phenolic moiety.…”

“…To a solution of N ‐acetylserotonin 5 [12] (1 g, 4.6 mmol) in dry THF, ethyl isocyanate (0.65 g, 9.2 mmol) and metallic sodium (2 mg) were added. The reaction mixture was stirred at RT for 2 hr under argon.…”