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...
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2021
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oai:doaj.org-article:2fa07dad42e84e84a166b83486acc9b52021-11-11T18:33:22ZHybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis10.3390/molecules262165731420-3049https://doaj.org/article/2fa07dad42e84e84a166b83486acc9b52021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6573https://doaj.org/toc/1420-3049Alzheimer’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, <sup>1</sup>H- and <sup>13</sup>C-NMR). In vitro inhibitory results revealed compound <b>5b</b> as a promising and lead inhibitor with an IC<sub>50</sub> value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC<sub>50</sub> = 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.Sumera ZaibRubina MunirMuhammad Tayyab YounasNaghmana KausarAliya IbrarSehar AqsaNoorma ShahidTahira Tasneem AsifHashem O. AlsaabImtiaz KhanMDPI AGarticlequinolinethiosemicarbazonemolecular designhybridizationAlzheimer’s diseaseneurodegenerationOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6573, p 6573 (2021) |
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DOAJ |
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| topic |
quinoline thiosemicarbazone molecular design hybridization Alzheimer’s disease neurodegeneration Organic chemistry QD241-441 |
| spellingShingle |
quinoline thiosemicarbazone molecular design hybridization Alzheimer’s disease neurodegeneration Organic chemistry QD241-441 Sumera Zaib Rubina Munir Muhammad Tayyab Younas Naghmana Kausar Aliya Ibrar Sehar Aqsa Noorma Shahid Tahira Tasneem Asif Hashem O. Alsaab Imtiaz Khan Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis |
| 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, <sup>1</sup>H- and <sup>13</sup>C-NMR). In vitro inhibitory results revealed compound <b>5b</b> as a promising and lead inhibitor with an IC<sub>50</sub> value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC<sub>50</sub> = 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 |
article |
| author |
Sumera Zaib Rubina Munir Muhammad Tayyab Younas Naghmana Kausar Aliya Ibrar Sehar Aqsa Noorma Shahid Tahira Tasneem Asif Hashem O. Alsaab Imtiaz Khan |
| author_facet |
Sumera Zaib Rubina Munir Muhammad Tayyab Younas Naghmana Kausar Aliya Ibrar Sehar Aqsa Noorma Shahid Tahira Tasneem Asif Hashem O. Alsaab Imtiaz Khan |
| author_sort |
Sumera Zaib |
| 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_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_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_sort |
hybrid quinoline-thiosemicarbazone therapeutics as a new treatment opportunity for alzheimer’s disease‒synthesis, in vitro cholinesterase inhibitory potential and computational modeling analysis |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/2fa07dad42e84e84a166b83486acc9b5 |
| work_keys_str_mv |
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