Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors

被引：44

作者：

Aslam, Sana ^{[1
,2
,3
]}

Zaib, Sumera ^{[4
]}

Ahmad, Matloob ^{[5
]}

Gardiner, John M. ^{[2
,3
]}

Ahmad, Aqeel ^{[2
,3
]}

Hameed, Abdul ^{[6
]}

Furtmann, Norbert ^{[7
]}

Guetschow, Michael ^{[7
]}

Bajorath, Juergen ^{[8
]}

Iqbal, Jamshed ^{[4
]}

机构：

[1] Govt Coll Women Univ, Dept Chem, Faisalabad 38000, Pakistan

[2] Univ Manchester, Sch Chem, Manchester M1 7DN, Lancs, England

[3] Univ Manchester, Manchester Inst Biotechnol, Manchester M1 7DN, Lancs, England

[4] COMSATS Inst Informat Technol, Ctr Adv Drug Res, Abbottabad 22060, Pakistan

[5] Govt Coll Univ, Dept Chem, Faisalabad 38000, Pakistan

[6] Univ Karachi, HEJ Res Inst Chem, Int Ctr Chem & Biol Sci, Karachi 32, Pakistan

[7] Univ Bonn, Inst Pharmaceut, D-53121 Bonn, Germany

[8] Univ Bonn, Dept Life Sci Informat, B IT, LIMES Program Unit Chem Biol & Med Chem, D-53113 Bonn, Germany

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 78卷

关键词：

Pyrazolobenzothiazine; Benzimidazole; Hybrid compounds; Cholinesterases; Docking studies; STRUCTURE-BASED DISCOVERY; ALZHEIMERS-DISEASE; DERIVATIVES; BUTYRYLCHOLINESTERASE; ACETYLCHOLINESTERASE; ANTIOXIDANT; 1,1-DIOXIDE; STRATEGY; LIGANDS; PROTEIN;

D O I：

10.1016/j.ejmech.2014.03.035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two series of novel pyrazolobenzothiazine-based hybrid compounds were efficiently synthesized starting from saccharin sodium salt. Pyrazolo[4,3-c][1,2]benzothiazine scaffolds were N-arylated by using p-fluorobenzaldehyde, followed by the incorporation of a benzimidazole or similar ring systems by treatment with arylenediamines. These phenylene-connected hybrid compounds were investigated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compounds 12d and 12k were the most potent AChE inhibitors with IC50 values of 11 and 13 nM, respectively, while 6j (IC50 = 17 nM) proved to be the most active inhibitor against BuChE with remarkable selectivity for BuChE over AChE. Molecular docking studies were also performed on human AChE and BuChE to suggest possible binding modes in which the inhibitor's extended structure is accommodated along the active site gorge of both enzymes. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：106 / 117

页数：12

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