Design, synthesis and biological assessment of acridine derivatives containing 1,3,4-thiadiazole moiety as novel selective acetylcholinesterase inhibitors

被引:27
作者
Lotfi, Safa [1 ]
Rahmani, Talat [2 ]
Hatami, Maryam [1 ]
Pouramiri, Behjat [3 ,6 ]
Kermani, Esmat Tavakolinejad [2 ]
Rezvannejad, Elham [1 ]
Mortazavi, Mojtaba [1 ]
Hafshejani, Shahnaz Fathi [1 ]
Askari, Nahid [1 ]
Pourjamali, Nader [4 ]
Zahedifar, Mahboobeh [5 ]
机构
[1] Grad Univ Adv Technol, Inst Sci & High Technol & Environm Sci, Dept Biotechnol, Kerman, Iran
[2] Shahid Bahonar Univ Kerman, Dept Chem, Fac Sci, Kerman, Iran
[3] Qom Univ Technol, Fac Basic Sci, Dept Chem, Qom 37195, Iran
[4] Jiroft Univ Med Sci, Deputy Dev & Resource Management, Jiroft, Iran
[5] Univ Jiroft, Fac Sci, Dept Chem, Jiroft 7867161167, Iran
[6] Jiroft Univ Med Sci, Student Res Comm, Jiroft, Iran
关键词
Acridine; 1,3,4-thiadiazol; Alzheimer's disease; Cholinesterase inhibitor; Molecular docking; BETA-AMYLOID AGGREGATION; ANTICHOLINESTERASE ACTIVITY; ALZHEIMERS; DOCKING; SITE; THERAPY; BINDING; AGENTS; ACHE;
D O I
10.1016/j.bioorg.2020.104457
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
A novel series of acridine derivatives containing substituted thiadiazol-2-amine moiety was synthesized via multi-component condensation reaction of dimedone, aromatic aldehyde and 5-aryl-1,3,4-thiadiazol-2-amines in the presence of LaCl3 as a catalyst under solvent-free conditions. Anticholinesterase (AChE and BuChE) activity evaluation of the derivatives showed that all the derivatives are capable of inhibiting both enzymes and are highly selective towards AChE. Among them, the ability of 4i and 4d with respective IC50 values of 0.002 and 0.006 mu M to inhibit AChE was higher than the reference compound tacrine (IC50 = 0.016 mu M). The kinetics studies demonstrated that 4i and 4d inhibit AChE through a competitive/non-competitive mixed mechanism. The HEPG2 cell viability assay evidenced that 4i and 4d significantly exhibit lower hepatotoxicity compared with tacrine. Blind docking experiments performed on TcAChE (PDB ID: 2ACE) indicated that an unknown site is preferred for binding by all the derivatives over classic binding site of the enzyme, site 1 (CAS/PAS). Identification of the residues by protein structure alignment confirmed that this site is site 2 which was recently recognized as a new allosteric site of hAChE. The binding modes of 4i and 4d were also investigated using local docking studies on site 1 and site 2.
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页数:14
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