Synthesis and biological evaluation of novel N,N'-bis-methylenedioxybenzyl-alkylenediamines as bivalent anti-Alzheimer disease ligands.
A novel series of N,N'-bis-methylenedioxybenzyl-alkylenediamines 5a-5g have been designed, synthesized and evaluated as bivalent anti-Alzheimer's disease ligands. The enzyme inhibition assay results indicated that compounds 5e-5g inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the micromolar range (IC(50), 2.76-4.24 µM for AChE and 3.02-5.14 µM for BuChE), which was in the same potential as the reference compound rivastigmine (IC(50), 5.50 µM for AChE and 1.60 µM for BuChE). It was found that compounds could bind simultaneously to the peripheral and catalytic sites of AChE. β-Amyloid (Aβ) aggregation inhibition assay results showed that compound 5e exhibited highest self-mediated Aβ fibril aggregation inhibition activity (40.3%) with a similar potential as curcumin (41.6%). It was also found that 5e-5g did not affect neuroblastoma cell viability at the concentration of 50 μM.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Wen
W
Luo
Yan-Ping
YP
Li
Jia-Heng
JH
Tan
Lian-Quan
LQ
Gu
Zhi-Shu
ZS
Huang
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008752:Methylene Chloride / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D001577:Benzophenones; D003959:Diamines; D004791:Enzyme Inhibitors; D008024:Ligands; D008752:Methylene Chloride; C004839:dioxybenzone; D003474:Curcumin