Neurodegeneration in Alzheimer’s disease (AD), is a devastating disorder accounting for the majority of the dementias.1 Despite the advances achieved over the last two decades in the understanding of the pathogenic mechanisms underlying AD, only a few drugs are currently available, which include AChE inhibitors (rivastigmine, galantamine, and donepezil), for the symptomatic relief of mild to moderate AD, and the N-methyl-D-aspartate receptor antagonist memantine.2 Previously, we reported the inhibitory activities of cholinesterases (ChEs) by a number of derivatives of annulated tetrahydroazocino-indoles, which preferentially inhibited AChE over BChE, with potency in the low micromolar range.3 New 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives have been synthesized and evaluated for their activity as ChEs’ inhibitors. The most potent compounds have been identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be highly potent inhibitors of human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships revealed critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). Interestingly, 12b increased the viability of SH-SY5Y cells pre-treated with 250 μM NMDA, with significant effects (P<0.05) at concentrations ranging from 0.5 to 5 μM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome.
AZEPINO [4,3-b]INDOLE DERIVATIVES AS SELECTIVE INHIBITORS OF HUMAN BUTYRYLCHOLINESTERASE WITH PROTECTIVE EFFECTS AGAINST NMDA-INDUCED NEUROTOXICITY
DE CANDIA, MODESTOWriting – Original Draft Preparation
;DENORA, NUNZIO;MAJELLARO, MARIA;CELLAMARE, Saverio;ALTOMARE, Cosimo DamianoSupervision
2016-01-01
Abstract
Neurodegeneration in Alzheimer’s disease (AD), is a devastating disorder accounting for the majority of the dementias.1 Despite the advances achieved over the last two decades in the understanding of the pathogenic mechanisms underlying AD, only a few drugs are currently available, which include AChE inhibitors (rivastigmine, galantamine, and donepezil), for the symptomatic relief of mild to moderate AD, and the N-methyl-D-aspartate receptor antagonist memantine.2 Previously, we reported the inhibitory activities of cholinesterases (ChEs) by a number of derivatives of annulated tetrahydroazocino-indoles, which preferentially inhibited AChE over BChE, with potency in the low micromolar range.3 New 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives have been synthesized and evaluated for their activity as ChEs’ inhibitors. The most potent compounds have been identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be highly potent inhibitors of human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships revealed critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). Interestingly, 12b increased the viability of SH-SY5Y cells pre-treated with 250 μM NMDA, with significant effects (P<0.05) at concentrations ranging from 0.5 to 5 μM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome.File | Dimensione | Formato | |
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