Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases : Synthesis, biological evaluation and docking study
Copyright © 2021 Elsevier Inc. All rights reserved..
A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Bioorganic chemistry - 116(2021) vom: 01. Nov., Seite 105301 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Krátký, Martin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.12.2021 Date Revised 14.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2021.105301 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330348965 |
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| 100 | 1 | |a Krátký, Martin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases |b Synthesis, biological evaluation and docking study |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 08.12.2021 | ||
| 500 | |a Date Revised 14.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Acetylcholinesterase | |
| 650 | 4 | |a Butyrylcholinesterase | |
| 650 | 4 | |a Enzyme inhibition | |
| 650 | 4 | |a Molecular docking | |
| 650 | 4 | |a Monoamine oxidases | |
| 650 | 4 | |a Multitargeting ligands | |
| 650 | 4 | |a Propargylamine | |
| 650 | 4 | |a Salicylic scaffold | |
| 650 | 7 | |a Antioxidants |2 NLM | |
| 650 | 7 | |a Cholinesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Monoamine Oxidase Inhibitors |2 NLM | |
| 650 | 7 | |a Propylamines |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a propargylamine |2 NLM | |
| 650 | 7 | |a 2450-71-7 |2 NLM | |
| 650 | 7 | |a Pargyline |2 NLM | |
| 650 | 7 | |a 9MV14S8G3E |2 NLM | |
| 650 | 7 | |a Monoamine Oxidase |2 NLM | |
| 650 | 7 | |a EC 1.4.3.4 |2 NLM | |
| 650 | 7 | |a Butyrylcholinesterase |2 NLM | |
| 650 | 7 | |a EC 3.1.1.8 |2 NLM | |
| 650 | 7 | |a Cholinesterases |2 NLM | |
| 650 | 7 | |a EC 3.1.1.8 |2 NLM | |
| 700 | 1 | |a Vu, Quynh Anh |e verfasserin |4 aut | |
| 700 | 1 | |a Štěpánková, Šárka |e verfasserin |4 aut | |
| 700 | 1 | |a Maruca, Annalisa |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Tiago Barros |e verfasserin |4 aut | |
| 700 | 1 | |a Ambrož, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Pflégr, Václav |e verfasserin |4 aut | |
| 700 | 1 | |a Rocca, Roberta |e verfasserin |4 aut | |
| 700 | 1 | |a Svrčková, Katarína |e verfasserin |4 aut | |
| 700 | 1 | |a Alcaro, Stefano |e verfasserin |4 aut | |
| 700 | 1 | |a Borges, Fernanda |e verfasserin |4 aut | |
| 700 | 1 | |a Vinšová, Jarmila |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:116 |g year:2021 |g day:01 |g month:11 |g pages:105301 |
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