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[摘要]：A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-beta (A beta)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC(50) = 8.0 mu M, BuChE IC(50) = 3.9 mu M) and hAChE-promoted A beta-aggregation inhibition (30.8% at 100 mu M), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC(50) = 10.0 mu M, BuChE IC(50) = 7.6 mu M) and hAChE-promoted A beta-aggregation inhibition (32% at 100 mu M). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides A beta-aggregation inhibition. (C) 2011 Elsevier Ltd. All rights reserved. |
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