Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities

被引：28

作者：

Ghobadian, Roshanak ^{[1
]}

Mahdavi, Mohammad ^{[2
]}

Nadri, Hamid ^{[3
,4
]}

Moradi, Alireza ^{[3
,4
]}

Edraki, Najmeh ^{[5
]}

Akbarzadeh, Tahmineh ^{[1
,6
]}

Sharifzadeh, Mohammad ^{[7
]}

Bukhari, Syed Nasir Abbas ^{[8
]}

Amini, Mohsen ^{[1
]}

机构：

[1] Univ Tehran Med Sci, Dept Med Chem, Fac Pharm, Tehran 14176, Iran

[2] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Endocrinol & Metab Clin Sci Inst, Tehran, Iran

[3] Shahid Sadoughi Univ Med Sci, Pharmaceut Sci Res Ctr, Yazd 8915173143, Iran

[4] Shahid Sadoughi Univ Med Sci, Fac Pharm, Yazd 8915173143, Iran

[5] Shiraz Univ Med Sci, Med & Nat Prod Chem Res Ctr, Shiraz, Iran

[6] Univ Tehran Med Sci, Persian Med & Pharm Res Ctr, Tehran, Iran

[7] Univ Tehran Med Sci, Dept Pharmacol & Toxicol, Fac Pharm, Tehran, Iran

[8] Jouf Univ, Dept Pharmaceut Chem, Coll Pharm, Al Jouf 2014, Sakaka, Saudi Arabia

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 155卷

关键词：

Alzheimer's disease; Butyrylcholinesterase; Docking study; 2,3,4,9-Tetrahydro-1H-carbazole; In-vitro assay; SITE ACETYLCHOLINESTERASE INHIBITORS; ALZHEIMERS-DISEASE; BIOLOGICAL EVALUATION; BUTYRYLCHOLINESTERASE INHIBITORS; DRUG CANDIDATES; IN-VITRO; DERIVATIVES; DESIGN; MOIETY; DOCKING;

D O I：

10.1016/j.ejmech.2018.05.031

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Butyrylcholinesterase (BuChE) inhibitors have become interesting target for treatment of Alzheimer's disease (AD). A series of dual binding site BuChE inhibitors were designed and synthesized based on 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. In-vitro assay revealed that all of the designed compounds were selective and potent BuChE inhibitors. The most potent BuChE inhibitor was compound 6i (IC50 = 0.088 +/- 0.0009 mu M) with the mixed-type inhibition. Docking study revealed that 6i is a dual binding site BuChE inhibitor. Also, Pharmacokinetic properties for 6i were accurate to Lipinski's rule. In addition, compound 6i demonstrated neuroprotective and beta-secretase (BACE1) inhibition activities. This compound could also inhibit AChE-induced and self-induced A beta peptide aggregation at concentration of 100 mu M and 10 mu M respectively. Generally, the results are presented as new potent selective BuChE inhibitors with a therapeutic potential for the treatment of AD. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：49 / 60

页数：12

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