New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity.
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 μM NMDA, with significant effects (P < 0.05) at concentrations between 0.5 and 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.
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Modesto
M
de Candia
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Giorgia
G
Zaetta
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Nunzio
N
Denora
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Domenico
D
Tricarico
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Maria
M
Majellaro
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Saverio
S
Cellamare
Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address: cosimodamiano.altomare@uniba.it.
Cosimo D
CD
Altomare
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000009:adverse effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D001381:Azepines; D002800:Cholinesterase Inhibitors; D007211:Indoles; D018696:Neuroprotective Agents; D016202:N-Methylaspartate; D002091:Butyrylcholinesterase
Alzheimer's disease; Azepino[4,3-b]indole; Butyrylcholinesterase; N-Methyl d-aspartate receptor; Neuroprotection