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Design, Synthesis, and Bioevaluation of Indole Core Containing 2-Arylidine Derivatives of Thiazolopyrimidine as Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B for the Treatment of Alzheimer Disease
[Image: see text] In continuation of our previous study to identify multitarget inhibitors of cholinesterases (ChEs) and monoamine oxidase (MAOs) isoforms, we synthesized and evaluated 2-arylidine derivatives of thiazolopyrimidine for the treatment of Alzheimer disease. Three series of compounds wit...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945123/ https://www.ncbi.nlm.nih.gov/pubmed/35350344 http://dx.doi.org/10.1021/acsomega.1c06344 |
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author | Shahid Nadeem, Muhammad Azam Khan, Jalaluddin Kazmi, Imran Rashid, Umer |
author_facet | Shahid Nadeem, Muhammad Azam Khan, Jalaluddin Kazmi, Imran Rashid, Umer |
author_sort | Shahid Nadeem, Muhammad |
collection | PubMed |
description | [Image: see text] In continuation of our previous study to identify multitarget inhibitors of cholinesterases (ChEs) and monoamine oxidase (MAOs) isoforms, we synthesized and evaluated 2-arylidine derivatives of thiazolopyrimidine for the treatment of Alzheimer disease. Three series of compounds with different linker size and target-anchoring functional groups were synthesized. Compounds 34–37 showed excellent to good AChE and BChE inhibition potential at nanomolar to low micromolar concentration. While all the compounds showed excellent MAO-B inhibition and selectivity relative to MAO-A, compounds 25 and 36 emerged as the most potent MAO-B inhibitors of all the series of synthesized compounds with IC(50) values of 0.13 μM and 0.10 μM, respectively. Furthermore, kinetic studies of inhibitor 35 showed mixed inhibition mode. Exploration of structure activity relationship (SAR) revealed the role of functionalities and length of linkers on potency. Acute toxicity evaluation showed the safety of tested compounds up to 2000 mg/kg dose. PAMPA-BBB evaluation showed BBB permeability of the tested compounds, while MTT assay performed on neuroblastoma SHSY5Y cells showed that all the tested compounds are non-neurotoxic in the tested concentrations. Docking studies showed a strong correlation with experimental in vitro results via binding orientations and interaction patterns of the synthesized compounds into the binding sites of target enzymes. We have successfully identified safe, non-neurotoxic, and blood brain barrier permeable multitarget lead compounds for the treatment of AD. |
format | Online Article Text |
id | pubmed-8945123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-89451232022-03-28 Design, Synthesis, and Bioevaluation of Indole Core Containing 2-Arylidine Derivatives of Thiazolopyrimidine as Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B for the Treatment of Alzheimer Disease Shahid Nadeem, Muhammad Azam Khan, Jalaluddin Kazmi, Imran Rashid, Umer ACS Omega [Image: see text] In continuation of our previous study to identify multitarget inhibitors of cholinesterases (ChEs) and monoamine oxidase (MAOs) isoforms, we synthesized and evaluated 2-arylidine derivatives of thiazolopyrimidine for the treatment of Alzheimer disease. Three series of compounds with different linker size and target-anchoring functional groups were synthesized. Compounds 34–37 showed excellent to good AChE and BChE inhibition potential at nanomolar to low micromolar concentration. While all the compounds showed excellent MAO-B inhibition and selectivity relative to MAO-A, compounds 25 and 36 emerged as the most potent MAO-B inhibitors of all the series of synthesized compounds with IC(50) values of 0.13 μM and 0.10 μM, respectively. Furthermore, kinetic studies of inhibitor 35 showed mixed inhibition mode. Exploration of structure activity relationship (SAR) revealed the role of functionalities and length of linkers on potency. Acute toxicity evaluation showed the safety of tested compounds up to 2000 mg/kg dose. PAMPA-BBB evaluation showed BBB permeability of the tested compounds, while MTT assay performed on neuroblastoma SHSY5Y cells showed that all the tested compounds are non-neurotoxic in the tested concentrations. Docking studies showed a strong correlation with experimental in vitro results via binding orientations and interaction patterns of the synthesized compounds into the binding sites of target enzymes. We have successfully identified safe, non-neurotoxic, and blood brain barrier permeable multitarget lead compounds for the treatment of AD. American Chemical Society 2022-03-10 /pmc/articles/PMC8945123/ /pubmed/35350344 http://dx.doi.org/10.1021/acsomega.1c06344 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Shahid Nadeem, Muhammad Azam Khan, Jalaluddin Kazmi, Imran Rashid, Umer Design, Synthesis, and Bioevaluation of Indole Core Containing 2-Arylidine Derivatives of Thiazolopyrimidine as Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B for the Treatment of Alzheimer Disease |
title | Design, Synthesis, and Bioevaluation of Indole Core
Containing 2-Arylidine Derivatives of Thiazolopyrimidine as
Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B
for the Treatment of Alzheimer Disease |
title_full | Design, Synthesis, and Bioevaluation of Indole Core
Containing 2-Arylidine Derivatives of Thiazolopyrimidine as
Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B
for the Treatment of Alzheimer Disease |
title_fullStr | Design, Synthesis, and Bioevaluation of Indole Core
Containing 2-Arylidine Derivatives of Thiazolopyrimidine as
Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B
for the Treatment of Alzheimer Disease |
title_full_unstemmed | Design, Synthesis, and Bioevaluation of Indole Core
Containing 2-Arylidine Derivatives of Thiazolopyrimidine as
Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B
for the Treatment of Alzheimer Disease |
title_short | Design, Synthesis, and Bioevaluation of Indole Core
Containing 2-Arylidine Derivatives of Thiazolopyrimidine as
Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B
for the Treatment of Alzheimer Disease |
title_sort | design, synthesis, and bioevaluation of indole core
containing 2-arylidine derivatives of thiazolopyrimidine as
multitarget inhibitors of cholinesterases and monoamine oxidase a/b
for the treatment of alzheimer disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945123/ https://www.ncbi.nlm.nih.gov/pubmed/35350344 http://dx.doi.org/10.1021/acsomega.1c06344 |
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