Title : New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity - de Candia_2016_Eur.J.Med.Chem_125_288 |
Author(s) : de Candia M , Zaetta G , Denora N , Tricarico D , Majellaro M , Cellamare S , Altomare CD |
Ref : Eur Journal of Medicinal Chemistry , 125 :288 , 2016 |
Abstract :
Several 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives were synthesized and evaluated for their activity as cholinesterase (ChE) inhibitors. The most potent inhibitors were identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be very active against human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships highlighted 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). The effects of a number of compounds against NMDA-induced SH-SY5Y neuronal cell injury were also evaluated. Treatment with 12b increased cell viability in SH-SY5Y cells pretreated with 250 muM NMDA, with significant effects (P < 0.05) at concentrations between 0.5 and 5 muM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome. |
PubMedSearch : de Candia_2016_Eur.J.Med.Chem_125_288 |
PubMedID: 27688184 |
Inhibitor | 6-(2-phenylethyl)-THAI-12b |
de Candia M, Zaetta G, Denora N, Tricarico D, Majellaro M, Cellamare S, Altomare CD (2016)
New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity
Eur Journal of Medicinal Chemistry
125 :288
de Candia M, Zaetta G, Denora N, Tricarico D, Majellaro M, Cellamare S, Altomare CD (2016)
Eur Journal of Medicinal Chemistry
125 :288