Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and A beta-aggregation inhibitors: Synthesis and biological evaluation

作者：Mohamed Tarek; Yeung Jacky C K; Rao Praveen P N^*

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(19): 5881-5887.

DOI：10.1016/j.bmcl.2011.07.091

• Cholinesterase inhibitors (ChEIs)
• Acetylcholinesterase (AChE)
• Butyrylcholinesterase (BuChE)
• Human acetylcholinesterase (hAChE)
• Structure-activity relationship (SAR)
• Amyloid-beta (A beta)
• 5,5 '-Dithiobis(2-nitrobenzoic acid) (DTNB)

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 IC50 = 8.0 mu M, BuChE IC50 = 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 IC50 = 10.0 mu M, BuChE IC50 = 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.

• 出版日期2011-10-1