Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions

被引：39

作者：

Mishra, Puja ^{[1
]}

Sharma, Piyoosh ^{[1
]}

Tripathi, Prabhash Nath ^{[1
]}

Gupta, Sukesh Kumar ^{[1
]}

Srivastava, Pavan ^{[1
]}

Seth, Ankit ^{[1
]}

Tripathi, Avanish ^{[1
]}

Krishnamurthy, Sairam ^{[1
]}

Shrivastava, Sushant Kumar ^{[1
]}

机构：

[1] Banaras Hindu Univ, Indian Inst Technol, Dept Pharmaceut Engn & Technol, Varanasi 221005, Uttar Pradesh, India

来源：

BIOORGANIC CHEMISTRY | 2019年 / 89卷

关键词：

Acetylcholinesterase; Butyrylcholinesterase; 1,3,4-Oxadiazole; Molecular hybridization; 4-Aminopyridine; BIOLOGICAL EVALUATION; 4-AMINOPYRIDINE DERIVATIVES; ALZHEIMERS-DISEASE; MOLECULAR-DYNAMICS; ACID-DERIVATIVES; ANTIOXIDANT; SITE; 1,2,4-TRIAZOLE; EPIDEMIOLOGY; AGGREGATION;

D O I：

10.1016/j.bioorg.2019.103025

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：

The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human choli-nesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50 = 1.098 mu M; Ki = 0.960 mu M). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced A beta aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.

引用

页数：13

共 61 条

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