Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection
Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment...
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MDPI AG
2021-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/6/1562 |
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| author | Jutamas Jiaranaikulwanitch Hataichanok Pandith Sarin Tadtong Phanit Thammarat Supat Jiranusornkul Nattapong Chauthong Supitcha Nilkosol Opa Vajragupta |
| author_facet | Jutamas Jiaranaikulwanitch Hataichanok Pandith Sarin Tadtong Phanit Thammarat Supat Jiranusornkul Nattapong Chauthong Supitcha Nilkosol Opa Vajragupta |
| author_sort | Jutamas Jiaranaikulwanitch |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds <b>2c</b> and <b>5c</b> exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds <b>2c</b> and <b>5c</b> were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2. |
| first_indexed | 2024-03-10T13:18:35Z |
| format | Article |
| id | doaj.art-a3936d1f81aa4949939a94561b8c76c8 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T13:18:35Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a3936d1f81aa4949939a94561b8c76c82023-11-21T10:13:30ZengMDPI AGMolecules1420-30492021-03-01266156210.3390/molecules26061562Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and NeuroprotectionJutamas Jiaranaikulwanitch0Hataichanok Pandith1Sarin Tadtong2Phanit Thammarat3Supat Jiranusornkul4Nattapong Chauthong5Supitcha Nilkosol6Opa Vajragupta7Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmacognosy, Faculty of Pharmacy, Srinakharinwirot University, Nakhonnayok 26120, ThailandDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, ThailandOffice of Research Affairs, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, ThailandAlzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds <b>2c</b> and <b>5c</b> exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds <b>2c</b> and <b>5c</b> were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.https://www.mdpi.com/1420-3049/26/6/1562ascorbic derivativesBACE1 inhibitoramyloid aggregation inhibitionantioxidantneuroprotectiveanti-inflammation |
| spellingShingle | Jutamas Jiaranaikulwanitch Hataichanok Pandith Sarin Tadtong Phanit Thammarat Supat Jiranusornkul Nattapong Chauthong Supitcha Nilkosol Opa Vajragupta Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection Molecules ascorbic derivatives BACE1 inhibitor amyloid aggregation inhibition antioxidant neuroprotective anti-inflammation |
| title | Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection |
| title_full | Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection |
| title_fullStr | Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection |
| title_full_unstemmed | Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection |
| title_short | Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection |
| title_sort | novel multifunctional ascorbic triazole derivatives for amyloidogenic pathway inhibition anti inflammation and neuroprotection |
| topic | ascorbic derivatives BACE1 inhibitor amyloid aggregation inhibition antioxidant neuroprotective anti-inflammation |
| url | https://www.mdpi.com/1420-3049/26/6/1562 |
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