Design, synthesis and biological evaluation of novel indanones derivatives as potent acetylcholinesterase/monoamine oxidase B inhibitors

被引：0

作者：

Hu, Zhaoxin ^{[1
]}

Zhou, Shengnan ^{[2
,3
]}

Li, Junda ^{[2
,3
]}

Li, Xinnan ^{[2
,3
]}

Zhou, Yang ^{[2
,3
]}

Zhu, Zheying ^{[4
]}

Xu, Jinyi ^{[2
,3
]}

Liu, Jie ^{[1
]}

机构：

[1] China Pharmaceut Univ, Sch Sci, Dept Organ Chem, Nanjing 211198, Peoples R China

[2] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 211198, Peoples R China

[3] China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Peoples R China

[4] Univ Nottingham, Sch Pharm, Univ Pk Campus, Nottingham NG7 2RD, England

来源：

FUTURE MEDICINAL CHEMISTRY | 2023年

基金：

中国国家自然科学基金;

关键词：

AChE; Alzheimer's disease; indan-1-one; MAO-B; MTDLs; ALZHEIMERS-DISEASE; MAO-A; LIGANDS; HYBRIDS; SEARCH; TARGET;

D O I：

10.4155/fmc-2023-0206

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aim: Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Results: These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound A1 possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC50 = 0.054 +/- 0.004 mu M; MAO-B: IC50 = 3.25 +/- 0.20 mu M), moderate inhibitory effects on self-mediated amyloid-beta (A beta) aggregation and antioxidant activity. In addition, compound A1 exhibited low neurotoxicity. More importantly, compound A1 showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. Conclusion: All results suggest that compound A1 may become a promising lead of anti-AD drug for further development.

引用

页码：1823 / 1841

页数：19

共 38 条

[1] Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer's Disease [J].

Agis-Torres, Angel ;

Soellhuber, Monica ;

Fernandez, Maria ;

Sanchez-Montero, J. M. .

CURRENT NEUROPHARMACOLOGY, 2014, 12 (01) :2-36

[2] Biological metals and metal-targeting compounds in major neurodegenerative diseases [J].

Barnham, Kevin J. ;

Bush, Ashley I. .

CHEMICAL SOCIETY REVIEWS, 2014, 43 (19) :6727-6749

[3] Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders [J].

Binda, C ;

Newton-Vinson, P ;

Hubálek, F ;

Edmondson, DE ;

Mattevi, A .

NATURE STRUCTURAL BIOLOGY, 2002, 9 (01) :22-26

[4] Amyloid-β and Tau The Trigger and Bullet in Alzheimer Disease Pathogenesis [J].

Bloom, George S. .

JAMA NEUROLOGY, 2014, 71 (04) :505-508

[5] Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents [J].

Carradori, Simone ;

Ortuso, Francesco ;

Petzer, Anel ;

Bagetta, Donatella ;

De Monte, Celeste ;

Secci, Daniela ;

De Vita, Daniela ;

Guglielmi, Paolo ;

Zengin, Gokhan ;

Aktumsek, Abdurrahman ;

Alcaro, Stefano ;

Petzer, Jacobus P. .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 143 :1543-1552

[6] A novel selective MAO-B inhibitor with neuroprotective and anti-Parkinsonian properties [J].

Chan, Hugh H. ;

Tse, Man Kit ;

Kumar, Saravana ;

Zhuo, Lang .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2018, 818 :254-262

[7] Three-dimensional structure of human monoamine oxidase A (MAO A): Relation to the structures of rat MAO A and human MAO B [J].

De Colibus, L ;

Li, M ;

Binda, C ;

Lustig, A ;

Edmondson, DE ;

Mattevi, A .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (36) :12684-12689

[8] Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity [J].

Eckert, Anne ;

Schmitt, Karen ;

Goetz, Juergen .

ALZHEIMERS RESEARCH & THERAPY, 2011, 3 (03)

[9] Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's disease patients [J].

Emilsson, L ;

Saetre, P ;

Balciuniene, J ;

Castensson, A ;

Cairns, N ;

Jazin, EE .

NEUROSCIENCE LETTERS, 2002, 326 (01) :56-60

[10] Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: Focus on modulation of CNS monoamine neurotransmitter release [J].

Finberg, John P. M. .

PHARMACOLOGY & THERAPEUTICS, 2014, 143 (02) :133-152

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