Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy

被引：8

作者：

Bautista-Aguilera, Oscar M. ^{[1
]}

Ismaili, Lhassane ^{[2
]}

Chioua, Mourad ^{[3
]}

Andrys, Rudolf ^{[4
]}

Schmidt, Monika ^{[4
]}

Bzonek, Petr ^{[4
]}

Angeles Martinez-Grau, Maria ^{[5
]}

Beadle, Christopher D. ^{[6
]}

Vetman, Tatiana ^{[7
]}

Lopez-Munoz, Francisco ^{[8
,9
]}

Iriepa, Isabel ^{[1
,10
]}

Refouvelet, Bernard ^{[2
]}

Musilek, Kamil ^{[4
]}

Marco-Contelles, Jose ^{[3
]}

机构：

[1] Alcala Univ, Dept Organ Chem & Inorgan Chem, Madrid 28805, Spain

[2] Univ Bourgogne Franche Comte, Neurosci Integrat & Clin EA 481, Lab Chim Organ & Therapeut, UFR Sante, 19 Rue Ambroise Pare, F-25000 Besancon, France

[3] CSIC, IQOG, Lab Med Chem, C Juan de la Cierva 3, Madrid 28006, Spain

[4] Univ Hradec Kralove, Fac Sci, Dept Chem, Rokitanskeho 62, Hradec Kralove 50003, Czech Republic

[5] Eli Lilly & Co, Lilly Res Labs, Avda Ind 30, Madrid 28108, Spain

[6] Eli Lilly & Co, Lilly Res Ctr, Windlesham GU20 6PH, Surrey, England

[7] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[8] Camilo Jose Cela Univ Madrid UCJC, Fac Hlth, Villafranca Del Castillo 28692, Spain

[9] Hosp 12 Octubre, Res Inst, Neuropsychopharmacol Unit, Madrid 28041, Spain

[10] Alcala Univ, Inst Chem Res Andres M del Rio, Madrid 28805, Spain

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2020年 / 21卷 / 11期

关键词：

Alzheimer's disease; ChE/MAO inhibition; contilisant; dihydroquinolinones; docking; quinolinones; synthesis; BIOLOGICAL EVALUATION; DRUG DISCOVERY; PREDICTION; SOLUBILITY; SCAFFOLD; DOCKING; OXIDASE;

D O I：

10.3390/ijms21113913

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：

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 mu M), with K-i value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.

引用

页码：1 / 20

页数：20

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