Alzheimer’s disease (AD) is a devastating disorder accounting for the majority of the dementias.1 Due to its multifactorial cause, and despite the advances achieved over the last two decades in the understanding of the AD pathogenic mechanisms, there are no effective therapies. So far, only few drugs are 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 Recently, we reported the inhibitory activities of cholinesterases (ChEs) by a number of 6- substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives.3 Among them, 6-(2-phenylethyl)-THAI 1, proved to be highly potent inhibitors of human BChE (IC50 = 13 nM), with 1000-fold selectivity over AChE. It showed additional neuroprotective effects on the SH-SY5Y cells viability, against NMDA- induced neurotoxicity. To overcome some drawbacks, such as a very low aqueous solubility (0.05 mg/mL) and a strong interaction with human serum albumin, which limit its use in vivo, compound 1 was chemically modified following the classical Mannich base approach.4 A number of derivatives (2), as potential prodrugs, were synthesized and tested. Herein, stability in physiological media, physicochemical properties, biological activities and preliminary biodistribution studies in animal models of type-2 derivatives are presented and discussed.
Alzheimer’s disease (AD) is a devastating disorder accounting for the majority of the dementias.1 Due to its multifactorial cause, and despite the advances achieved over the last two decades in the understanding of the AD pathogenic mechanisms, there are no effective therapies. So far, only few drugs are 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 Recently, we reported the inhibitory activities of cholinesterases (ChEs) by a number of 6- substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives.3 Among them, 6-(2-phenylethyl)-THAI 1, proved to be highly potent inhibitors of human BChE (IC50 = 13 nM), with 1000-fold selectivity over AChE. It showed additional neuroprotective effects on the SH-SY5Y cells viability, against NMDA- induced neurotoxicity. To overcome some drawbacks, such as a very low aqueous solubility (0.05 mg/mL) and a strong interaction with human serum albumin, which limit its use in vivo, compound 1 was chemically modified following the classical Mannich base approach.4 A number of derivatives (2), as potential prodrugs, were synthesized and tested. Herein, stability in physiological media, physicochemical properties, biological activities and preliminary biodistribution studies in animal models of type-2 derivatives are presented and discussed.
Synthesis and biological evaluation of Mannich base derivatives of the neuroprotective 6-(2-phenylethyl)-3,4,5,6-tetrahydroazepino[4,3- b]indol-1(2H)-one
DE CANDIA, Modesto;Purgatorio, Rosa;Morgese, MARIA GRAZIA;Cellamare, Saverio;Bolognino, Isabella;Altomare, Cosimo D.
2018-01-01
Abstract
Alzheimer’s disease (AD) is a devastating disorder accounting for the majority of the dementias.1 Due to its multifactorial cause, and despite the advances achieved over the last two decades in the understanding of the AD pathogenic mechanisms, there are no effective therapies. So far, only few drugs are 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 Recently, we reported the inhibitory activities of cholinesterases (ChEs) by a number of 6- substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives.3 Among them, 6-(2-phenylethyl)-THAI 1, proved to be highly potent inhibitors of human BChE (IC50 = 13 nM), with 1000-fold selectivity over AChE. It showed additional neuroprotective effects on the SH-SY5Y cells viability, against NMDA- induced neurotoxicity. To overcome some drawbacks, such as a very low aqueous solubility (0.05 mg/mL) and a strong interaction with human serum albumin, which limit its use in vivo, compound 1 was chemically modified following the classical Mannich base approach.4 A number of derivatives (2), as potential prodrugs, were synthesized and tested. Herein, stability in physiological media, physicochemical properties, biological activities and preliminary biodistribution studies in animal models of type-2 derivatives are presented and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
