The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies
An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535221002264 |
| _version_ | 1819000802285453312 |
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| author | Muhammad Mansha Muhammad Taha El Hassane Anouar Nisar Ullah |
| author_facet | Muhammad Mansha Muhammad Taha El Hassane Anouar Nisar Ullah |
| author_sort | Muhammad Mansha |
| collection | DOAJ |
| description | An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE) is important to prolong ACh activity in synapses for the enhanced cholinergic neurotransmission. In this study, a series of new fluoroquinolone derivatives (7a-m) have synthesized and evaluated for AChE and BChE inhibitory activities. The screening results suggested that 7 g bearing ortho fluorophenyl was the most active inhibitor against both AChE and BChE, exhibiting IC50 values of 0.70 ± 0.10 µM and 2.20 ± 0.10 µM, respectively. The structure–activity relationship (SAR) revealed that compounds containing electronegative functions (F, Cl, OMe, N and O) at the ortho position of the phenyl group exhibited higher activities as compared to their meta- and/or para substituted counterparts. Molecular docking studies of synthesized compounds 7a, 7g, 7j and 7l docked into the active site of AChE and 7a-f docked into the active site of BChE revealed that these compounds exhibited conventional H-bonding along with π-π interaction with the active residues of AChE through their electronegative functions and phenyl ring, respectively. All the synthesized compounds are characterized by spectroscopic methods including FT-IR, 1H- and 13C NMR as well as elemental analysis. This is the first example of fluoroquinolone-based cholinesterase inhibitors. |
| first_indexed | 2024-12-20T22:39:06Z |
| format | Article |
| id | doaj.art-39744749a56c49e4a009abeb670a68a4 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-12-20T22:39:06Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-39744749a56c49e4a009abeb670a68a42022-12-21T19:24:30ZengElsevierArabian Journal of Chemistry1878-53522021-07-01147103211The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studiesMuhammad Mansha0Muhammad Taha1El Hassane Anouar2Nisar Ullah3Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi ArabiaDepartment of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi ArabiaDepartment of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi ArabiaChemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia; Corresponding author.An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE) is important to prolong ACh activity in synapses for the enhanced cholinergic neurotransmission. In this study, a series of new fluoroquinolone derivatives (7a-m) have synthesized and evaluated for AChE and BChE inhibitory activities. The screening results suggested that 7 g bearing ortho fluorophenyl was the most active inhibitor against both AChE and BChE, exhibiting IC50 values of 0.70 ± 0.10 µM and 2.20 ± 0.10 µM, respectively. The structure–activity relationship (SAR) revealed that compounds containing electronegative functions (F, Cl, OMe, N and O) at the ortho position of the phenyl group exhibited higher activities as compared to their meta- and/or para substituted counterparts. Molecular docking studies of synthesized compounds 7a, 7g, 7j and 7l docked into the active site of AChE and 7a-f docked into the active site of BChE revealed that these compounds exhibited conventional H-bonding along with π-π interaction with the active residues of AChE through their electronegative functions and phenyl ring, respectively. All the synthesized compounds are characterized by spectroscopic methods including FT-IR, 1H- and 13C NMR as well as elemental analysis. This is the first example of fluoroquinolone-based cholinesterase inhibitors.http://www.sciencedirect.com/science/article/pii/S1878535221002264Fluoroquinolone derivativesAcetylcholinesteraseButyrylcholinesteraseMolecular dockingSAR |
| spellingShingle | Muhammad Mansha Muhammad Taha El Hassane Anouar Nisar Ullah The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies Arabian Journal of Chemistry Fluoroquinolone derivatives Acetylcholinesterase Butyrylcholinesterase Molecular docking SAR |
| title | The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies |
| title_full | The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies |
| title_fullStr | The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies |
| title_full_unstemmed | The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies |
| title_short | The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis, biological evaluation and in silico docking studies |
| title_sort | design of fluoroquinolone based cholinesterase inhibitors synthesis biological evaluation and in silico docking studies |
| topic | Fluoroquinolone derivatives Acetylcholinesterase Butyrylcholinesterase Molecular docking SAR |
| url | http://www.sciencedirect.com/science/article/pii/S1878535221002264 |
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