Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson’s disease

Affini, Anna; Hagenow, Stefanie; Živković, Aleksandra; Marco‐Contelles, José; Stark, Holger

doi:10.1016/j.ejmech.2018.02.015

Cited by 44 publications

(39 citation statements)

References 42 publications

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“…Monoamine oxidase A/B inhibition assays were performed as described previously using the discontinuous fluorimetric method with kynuramine as MAO substrate. 21 For the screening (test concentration: 10 −6 M) and IC 50 Figure S12 in supplemental material) or set to zero in case when the bottom plateau was not reached with highest concentration tested (leading to "IC 50 estimates").…”

Section: Enzymologymentioning

confidence: 99%

“…Reversibility of inhibition was confirmed via preincubation of inhibitor (10 ⨰ IC 50 in preincubation setting) with MAO B (10 ng µL −1 in preincubation setting) for 0, 30, 60 and 90 min (37°C), followed by 50⨰ dilution in buffer and assayed with an excess of substrate (10 ⨰ K M final concentration) as described above. 21 Data were calculated as percentage of vehicle control (DMSO; set to 100% enzyme activity remained) for each time point.…”

Section: Enzymologymentioning

confidence: 99%

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<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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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 (IC 50 = 56 nM, K i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC 50 = 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.

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Section: Enzymologymentioning

confidence: 99%

Section: Enzymologymentioning

confidence: 99%

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

Self Cite

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show abstract

“…PD had a high morbidity, and drug therapy represented by dopaminergic drugs was a main treatment method for PD [ 15 ]. Nevertheless, anti-Parkinson's disease drugs mainly acted on dopamine metabolism and cholinergic metabolic pathways instead of the apoptosis mechanism of dopaminergic neuron, so it can neither inhibit the progress of the disease effectively nor cure the disease.…”

Section: Discussionmentioning

confidence: 99%

Potential Therapeutic Drugs for Parkinson’s Disease Based on Data Mining and Bioinformatics Analysis

Chen

et al. 2018

Parkinson's Disease

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The objective is to search potential therapeutic drugs for Parkinson's disease based on data mining and bioinformatics analysis and providing new ideas for research studies on “new application of conventional drugs.” Method differential gene candidates were obtained based on data mining of genes of PD brain tissue, original gene data analysis, differential gene crossover, pathway enrichment analysis, and protein interaction, and potential therapeutic drugs for Parkinson's disease were obtained through drug-gene relationship. Result. 250 common differential genes were obtained from 3 research studies, and 31 differential gene candidates were obtained through gene enrichment analysis and protein interaction. 10 drugs such as metformin hydrochloride were directly or indirectly correlated to differential gene candidates. Conclusion. Potential therapeutic drugs that may be used for prevention and treatment of Parkinson's disease were discovered through data mining and bioinformatics analysis, which provided new ideas for research and development of drugs. Results showed that metformin hydrochloride and other drugs had certain therapeutical effect on Parkinson's disease, and melbine (DMBG) can be used for treatment of Parkinson's disease and type 2 diabetes patients.

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“…MAO A and B inhibition capacities were investigated using a discontinuous fluorimetric assay (Meiring et al, 2013 ) as described previously by using human recombinant membrane-bound MAO purchased from Sigma-Aldrich (Affini et al, 2018 ). Briefly, remained enzyme activity with inhibitor, either 1 μM (one-point) or concentrations ranging from 0.0001 to 10 μM, was assessed in the presence of kynuramine [2 × K M , K M = 20 μM (MAO A), K M = 30 μM (MAO B)] in potassium phosphate buffer (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

Selenazolyl-hydrazones as Novel Selective MAO Inhibitors With Antiproliferative and Antioxidant Activities: Experimental and In-silico Studies

et al. 2018

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The novel approach in the treatment of complex multifactorial diseases, such as neurodegenerative disorders and cancer, requires a development of efficient multi-targeting oriented drugs. Since oxidative stress significantly contributes to the pathogenesis of cancer and neurodegenerative disorders, potential drug candidates should possess good antioxidant properties. Due to promising biological activities shown for structurally related (1,3-thiazol-2-yl)hydrazones, a focused library of 12 structurally related benzylidene-based (1,3-selenazol-2-yl)hydrazones was designed as potential multi-targeting compounds. Monoamine oxidases (MAO) A/B inhibition properties of this class of compounds have been investigated. Surprisingly, the p-nitrophenyl-substituted (1,3-selenazol-2-yl)hydrazone 4 showed MAO B inhibition in a nanomolar concentration range (IC50 = 73 nM). Excellent antioxidant properties were confirmed in a number of different in vitro assays. Antiproliferative activity screening on a panel of six human solid tumor cell lines showed that potencies of some of the investigated compounds was comparable or even better than that of the positive control 5-fluorouracil. In-silico calculations of ADME properties pointed to promising good pharmacokinetic profiles of investigated compounds. Docking studies suggest that some compounds, compared to positive controls, have the ability to strongly interact with targets relevant to cancer such as 5′-nucleotidase, and to neurodegenerative diseases such as the small conductance calcium-activated potassium channel protein 1, in addition to confirmation of inhibitory binding at MAO B.

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Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson’s disease

Cited by 44 publications

References 42 publications

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Potential Therapeutic Drugs for Parkinson’s Disease Based on Data Mining and Bioinformatics Analysis

Selenazolyl-hydrazones as Novel Selective MAO Inhibitors With Antiproliferative and Antioxidant Activities: Experimental and In-silico Studies

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