In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease
Abstract Alzheimer’s disease (AD) necessitates innovative therapeutic approaches that target its multifaceted pathology. This study investigates a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as potential multi-target ligands for AD, aiming to simultaneously inhibit acet...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-98182-x |
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| author | Mourad Aloui Mohamed El fadili Somdutt Mujwar Mohammed Er-rajy Hatem A. Abuelizz Sara Er-rahmani Sara Zarougui Elhalaoui Menana |
| author_facet | Mourad Aloui Mohamed El fadili Somdutt Mujwar Mohammed Er-rajy Hatem A. Abuelizz Sara Er-rahmani Sara Zarougui Elhalaoui Menana |
| author_sort | Mourad Aloui |
| collection | DOAJ |
| description | Abstract Alzheimer’s disease (AD) necessitates innovative therapeutic approaches that target its multifaceted pathology. This study investigates a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as potential multi-target ligands for AD, aiming to simultaneously inhibit acetylcholinesterase (AChE) and amyloid-beta (Aβ) aggregation. To assess the therapeutic potential of these compounds, we employed a comprehensive computational approach, incorporating 2D-QSAR modeling, molecular dynamics simulations, molecular docking, and ADMET property analysis. Based on these analyses, we designed 13 novel pyridazine derivatives exhibiting favorable interactions with key AD-related proteins, enhanced dynamic stability within protein binding sites, and adherence to established drug-likeness principles. Notably, these compounds demonstrated promising oral absorption (96%) and exhibited no significant toxicity in preliminary assessments. These results indicate that the novel pyridazine derivatives warrant further investigation as promising multifunctional agents for the treatment of Alzheimer’s disease. |
| format | Article |
| id | doaj-art-4557b3edefba41baa8e5ef2fb1a744ab |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-4557b3edefba41baa8e5ef2fb1a744ab2025-08-20T02:15:02ZengNature PortfolioScientific Reports2045-23222025-05-0115112710.1038/s41598-025-98182-xIn silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s diseaseMourad Aloui0Mohamed El fadili1Somdutt Mujwar2Mohammed Er-rajy3Hatem A. Abuelizz4Sara Er-rahmani5Sara Zarougui6Elhalaoui Menana7LIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah UniversityLIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah UniversityChitkara College of Pharmacy, Chitkara UniversityLIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDipartimento Di Chimica, Università di TorinoLIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah UniversityLIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah UniversityAbstract Alzheimer’s disease (AD) necessitates innovative therapeutic approaches that target its multifaceted pathology. This study investigates a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as potential multi-target ligands for AD, aiming to simultaneously inhibit acetylcholinesterase (AChE) and amyloid-beta (Aβ) aggregation. To assess the therapeutic potential of these compounds, we employed a comprehensive computational approach, incorporating 2D-QSAR modeling, molecular dynamics simulations, molecular docking, and ADMET property analysis. Based on these analyses, we designed 13 novel pyridazine derivatives exhibiting favorable interactions with key AD-related proteins, enhanced dynamic stability within protein binding sites, and adherence to established drug-likeness principles. Notably, these compounds demonstrated promising oral absorption (96%) and exhibited no significant toxicity in preliminary assessments. These results indicate that the novel pyridazine derivatives warrant further investigation as promising multifunctional agents for the treatment of Alzheimer’s disease.https://doi.org/10.1038/s41598-025-98182-xQSARPyridazineMolecular dockingMolecular dynamicADMET proprietyAlzheimer’s disease |
| spellingShingle | Mourad Aloui Mohamed El fadili Somdutt Mujwar Mohammed Er-rajy Hatem A. Abuelizz Sara Er-rahmani Sara Zarougui Elhalaoui Menana In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease Scientific Reports QSAR Pyridazine Molecular docking Molecular dynamic ADMET propriety Alzheimer’s disease |
| title | In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease |
| title_full | In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease |
| title_fullStr | In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease |
| title_full_unstemmed | In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease |
| title_short | In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer’s disease |
| title_sort | in silico design of novel pyridazine derivatives as balanced multifunctional agents against alzheimer s disease |
| topic | QSAR Pyridazine Molecular docking Molecular dynamic ADMET propriety Alzheimer’s disease |
| url | https://doi.org/10.1038/s41598-025-98182-x |
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