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Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities

In this investigation, a number of phenoxyindole derivatives were designed, synthesized, and tested for their neuroprotective ability on SK-N-SH cells against Aβ(42)-induced cell death and biologically specific activities involved in anti-Aβ aggregation, anti-AChE, and antioxidant effects. The propo...

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Autores principales: Laivut, Somjate, Moongkarndi, Primchanien, Kitphati, Worawan, Rukthong, Pattarawit, Sathirakul, Korbtham, Sripha, Kittisak
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051485/
https://www.ncbi.nlm.nih.gov/pubmed/36986454
http://dx.doi.org/10.3390/ph16030355
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author Laivut, Somjate
Moongkarndi, Primchanien
Kitphati, Worawan
Rukthong, Pattarawit
Sathirakul, Korbtham
Sripha, Kittisak
author_facet Laivut, Somjate
Moongkarndi, Primchanien
Kitphati, Worawan
Rukthong, Pattarawit
Sathirakul, Korbtham
Sripha, Kittisak
author_sort Laivut, Somjate
collection PubMed
description In this investigation, a number of phenoxyindole derivatives were designed, synthesized, and tested for their neuroprotective ability on SK-N-SH cells against Aβ(42)-induced cell death and biologically specific activities involved in anti-Aβ aggregation, anti-AChE, and antioxidant effects. The proposed compounds, except compounds 9 and 10, could protect SK-N-SH cells at the IC(50) of anti-Aβ aggregation with cell viability values ranging from 63.05% ± 2.70% to 87.90% ± 3.26%. Compounds 3, 5, and 8 demonstrated striking relationships between the %viability of SK-N-SH cells and IC(50) values of anti-Aβ aggregation and antioxidants. No significant potency of all synthesized compounds against AChE was found. Among them, compound 5 showed the strongest anti-Aβ and antioxidant properties with IC(50) values of 3.18 ± 0.87 and 28.18 ± 1.40 μM, respectively. The docking data on the monomeric Aβ peptide of compound 5 demonstrated good binding at regions involved in the aggregation process, and the structural feature made it possible to be a superior radical scavenger. The most effective neuroprotectant belonged to compound 8, with a cell viability value of 87.90% ± 3.26%. Its unique mechanisms for enhancing the protective impact may serve additional purposes since it demonstrated mild biological-specific effects. In silico prediction of CNS penetration shows strong passive penetration ability across the blood–brain barrier from blood vessels to the CNS for compound 8. In light of our findings, compounds 5 and 8 appeared as potentially intriguing lead compounds for new therapeutic approaches to Alzheimer’s disease. More in vivo testing will be revealed in due course.
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spelling pubmed-100514852023-03-30 Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities Laivut, Somjate Moongkarndi, Primchanien Kitphati, Worawan Rukthong, Pattarawit Sathirakul, Korbtham Sripha, Kittisak Pharmaceuticals (Basel) Article In this investigation, a number of phenoxyindole derivatives were designed, synthesized, and tested for their neuroprotective ability on SK-N-SH cells against Aβ(42)-induced cell death and biologically specific activities involved in anti-Aβ aggregation, anti-AChE, and antioxidant effects. The proposed compounds, except compounds 9 and 10, could protect SK-N-SH cells at the IC(50) of anti-Aβ aggregation with cell viability values ranging from 63.05% ± 2.70% to 87.90% ± 3.26%. Compounds 3, 5, and 8 demonstrated striking relationships between the %viability of SK-N-SH cells and IC(50) values of anti-Aβ aggregation and antioxidants. No significant potency of all synthesized compounds against AChE was found. Among them, compound 5 showed the strongest anti-Aβ and antioxidant properties with IC(50) values of 3.18 ± 0.87 and 28.18 ± 1.40 μM, respectively. The docking data on the monomeric Aβ peptide of compound 5 demonstrated good binding at regions involved in the aggregation process, and the structural feature made it possible to be a superior radical scavenger. The most effective neuroprotectant belonged to compound 8, with a cell viability value of 87.90% ± 3.26%. Its unique mechanisms for enhancing the protective impact may serve additional purposes since it demonstrated mild biological-specific effects. In silico prediction of CNS penetration shows strong passive penetration ability across the blood–brain barrier from blood vessels to the CNS for compound 8. In light of our findings, compounds 5 and 8 appeared as potentially intriguing lead compounds for new therapeutic approaches to Alzheimer’s disease. More in vivo testing will be revealed in due course. MDPI 2023-02-25 /pmc/articles/PMC10051485/ /pubmed/36986454 http://dx.doi.org/10.3390/ph16030355 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Laivut, Somjate
Moongkarndi, Primchanien
Kitphati, Worawan
Rukthong, Pattarawit
Sathirakul, Korbtham
Sripha, Kittisak
Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities
title Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities
title_full Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities
title_fullStr Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities
title_full_unstemmed Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities
title_short Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities
title_sort design, synthesis, and neuroprotective activity of phenoxyindole derivatives on antiamyloid beta (aβ) aggregation, antiacetylcholinesterase, and antioxidant activities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051485/
https://www.ncbi.nlm.nih.gov/pubmed/36986454
http://dx.doi.org/10.3390/ph16030355
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