Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs

被引:22
作者
Hagenow, Jens [1 ]
Hagenow, Stefanie [1 ]
Grau, Kathrin [1 ]
Khanfar, Mohammad [1 ,2 ,3 ]
Hefke, Lena [4 ]
Proschak, Ewgenij [4 ]
Stark, Holger [1 ]
机构
[1] Heinrich Heine Univ Dusseldorf, Inst Pharmaceut & Med Chem, Univ Str 1, D-40225 Dusseldorf, Germany
[2] Univ Jordan, Fac Pharm, Amman 11942, Jordan
[3] Alfaisal Univ, Coll Pharm, Riyadh 11533, Saudi Arabia
[4] Goethe Univ Frankfurt, Inst Pharmaceut Chem, D-60438 Frankfurt, Germany
来源
DRUG DESIGN DEVELOPMENT AND THERAPY | 2020年 / 14卷
关键词
salicylic acid derivatives; molecular modeling; Parkinson's disease; enzyme inhibitor; pharmacophore; structure-activity relationships; MONOAMINE-OXIDASE B; ANTIMICROBIAL ACTIVITY; BIOLOGICAL EVALUATION; ANTIMYCOBACTERIAL ACTIVITY; POTENT INHIBITORS; DERIVATIVES; SALICYLANILIDES; ALDEHYDES; DISCOVERY; AMIDES;
D O I
10.2147/DDDT.S236586
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors. Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results. Results: N-(2,4-Dinitrophenyl)benzo [d] [1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC50 = 56 nM, K-i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC50 = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites. Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.
引用
收藏
页码:371 / 393
页数:23
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