Rational design and synthesis of dihydropyrimidine based dual binding site acetylcholinesterase inhibitors

被引：81

作者：

Ahmad, Sufyan ^{[1
]}

Iftikhar, Fatima ^{[1
]}

Ullah, Farhat ^{[2
]}

Sadiq, Abdul ^{[2
]}

Rashid, Umer ^{[1
,3
]}

机构：

[1] Hazara Univ, Dept Chem, Mansehra 21120, Pakistan

[2] Univ Malakand, Dept Pharm, Chakdara 18000, Dir L, Pakistan

[3] COMSATS Inst Informat Technol, Dept Chem, Abbottabad 22060, Pakistan

来源：

BIOORGANIC CHEMISTRY | 2016年 / 69卷

关键词：

Acetylcholinesterase; Butyrylcholinesterase; Dihydropyrimidines; Blood brain barrier; Dual binding site; BIOLOGICAL EVALUATION; ALZHEIMERS-DISEASE; DERIVATIVES; POTENT; DOCKING; IDENTIFICATION; MONASTROL; ANALOGS;

D O I：

10.1016/j.bioorg.2016.10.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Based on the pharmacological importance of dihydropyrimidine (DHPM) scaffold, substituted DHPMs linked with acetamide linker to substituted aromatic anilines were synthesized and evaluated for their potency as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The good AChE inhibitory activity of 4-dihydropyrimidine-2-thione (4a-h) and 2-amino-1,4-dihyropyrimidines (5a-h) series was observed with compound 4a and 4d identified as the most potent compounds with IC50 values of 0.17 +/- 0.01 and 0.39 +/- 0.04 mu M respectively. The inhibition of BChE was found in a broader range of concentrations (2.37-56.32 mu M). To explore the binding insights into the enzyme, molecular docking study was carried out using GOLD software. The binding mode analysis indicated that all of these inhibitors are well accommodated in the active site and interact with the key amino acid residues of Catalytic anionic site (CAS) and peripheral anionic site (PAS). Furthermore, in silico ADMET predictions suggest that these compounds are non-AMES toxic with good blood brain barrier (BBB) penetration, human intestinal absorption. (C) 2016 Elsevier Inc. All rights reserved.

引用

页码：91 / 101

页数：11

共 26 条

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