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Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, los...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587653/ https://www.ncbi.nlm.nih.gov/pubmed/34770983 http://dx.doi.org/10.3390/molecules26216573 |
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author | Zaib, Sumera Munir, Rubina Younas, Muhammad Tayyab Kausar, Naghmana Ibrar, Aliya Aqsa, Sehar Shahid, Noorma Asif, Tahira Tasneem Alsaab, Hashem O. Khan, Imtiaz |
author_facet | Zaib, Sumera Munir, Rubina Younas, Muhammad Tayyab Kausar, Naghmana Ibrar, Aliya Aqsa, Sehar Shahid, Noorma Asif, Tahira Tasneem Alsaab, Hashem O. Khan, Imtiaz |
author_sort | Zaib, Sumera |
collection | PubMed |
description | Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, (1)H- and (13)C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC(50) value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC(50) = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease. |
format | Online Article Text |
id | pubmed-8587653 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85876532021-11-13 Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis Zaib, Sumera Munir, Rubina Younas, Muhammad Tayyab Kausar, Naghmana Ibrar, Aliya Aqsa, Sehar Shahid, Noorma Asif, Tahira Tasneem Alsaab, Hashem O. Khan, Imtiaz Molecules Article Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, (1)H- and (13)C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC(50) value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC(50) = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease. MDPI 2021-10-30 /pmc/articles/PMC8587653/ /pubmed/34770983 http://dx.doi.org/10.3390/molecules26216573 Text en © 2021 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 Zaib, Sumera Munir, Rubina Younas, Muhammad Tayyab Kausar, Naghmana Ibrar, Aliya Aqsa, Sehar Shahid, Noorma Asif, Tahira Tasneem Alsaab, Hashem O. Khan, Imtiaz Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
title | Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
title_full | Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
title_fullStr | Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
title_full_unstemmed | Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
title_short | Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
title_sort | hybrid quinoline-thiosemicarbazone therapeutics as a new treatment opportunity for alzheimer’s disease‒synthesis, in vitro cholinesterase inhibitory potential and computational modeling analysis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587653/ https://www.ncbi.nlm.nih.gov/pubmed/34770983 http://dx.doi.org/10.3390/molecules26216573 |
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