Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease
Alzheimer's disease (AD) is one of the most debilitating forms of amyloidogenesis-induced dementia, and innovative, effective scaffolds are required for its treatment. Monoamine oxidase B (MAO-B) contributes to Alzheimer's by oxidizing monoamines and generating reactive oxygen species, the...
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Elsevier
2025-07-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211715625003261 |
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| author | Tajamul Hussain Salman Alrokayan Dilawar Hussain Khurram Shoaib Syeda Abida Ejaz Steven Ford Jamshed Iqbal |
| author_facet | Tajamul Hussain Salman Alrokayan Dilawar Hussain Khurram Shoaib Syeda Abida Ejaz Steven Ford Jamshed Iqbal |
| author_sort | Tajamul Hussain |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is one of the most debilitating forms of amyloidogenesis-induced dementia, and innovative, effective scaffolds are required for its treatment. Monoamine oxidase B (MAO-B) contributes to Alzheimer's by oxidizing monoamines and generating reactive oxygen species, thereby increasing oxidative stress and neuroinflammation. This makes MAO-B a promising therapeutic target to mitigate neuronal damage and slow disease progression. Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate-determining step in the production of a peptide, hence its inhibitors may play a crucial role in the treatment of Alzheimer's disease. Therefore, the successful inhibition of BACE1 by small compounds may be a viable strategy for the development of anti-AD drugs. In the current investigation, a small library of aminoquinazolinone-hydrazone derivatives underwent in-vitro and in-silico investigations. The anti-proliferative and antioxidant activities of aminoquinazolin-4(3H)-one derivatives (DH1-DH8) were evaluated, along with their cytotoxicity toward non-cancerous BHK-21 cells. Among the tested compounds, DH5 and DH7 exhibited the highest potency against cancer cells. Secondly, the study investigated their antioxidant potential using DPPH and ABTS assays. Notably, DH3, DH5, and DH8 demonstrated strong radical scavenging activity, with DH8 showing the highest ABTS scavenging potential. Structure-activity relationship (SAR) analysis revealed that electron-donating groups (-OH, -OMe) enhanced antioxidant and anti-proliferative activity, while hydrophobic (Cl) groups contributed to increased cytotoxicity against cancer cells. The newly synthesized compounds were also tested for BACE1 inhibition in-vitro using fluorescence resonance energy transfer (FRET) test methods. Among these compounds, the 2-nitrobenzylidene-containing compound (DH8) exhibited the strongest inhibitory action against BACE1, with an IC50 of 5.75 μM. Furthermore, during molecular docking studies, DH8 also demonstrated the maximum binding energy of −8.3 kcal/mol. These findings were further supported by molecular dynamics (MD) simulations, indicating the substantial stability of the protein-ligand complex. Additionally, in-silico ADME modeling was utilized to analyze the pharmacokinetic profile. Conclusively, the findings of the current study suggest hydrazineylquinazolinones as valuable scaffolds for the treatment of Alzheimer's disease by targeting BACE1. |
| format | Article |
| id | doaj-art-775ee814179c4e58bcb85a3d350664e3 |
| institution | Kabale University |
| issn | 2211-7156 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | Results in Chemistry |
| spelling | doaj-art-775ee814179c4e58bcb85a3d350664e32025-08-20T03:39:09ZengElsevierResults in Chemistry2211-71562025-07-011610234310.1016/j.rechem.2025.102343Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's diseaseTajamul Hussain0Salman Alrokayan1Dilawar Hussain2Khurram Shoaib3Syeda Abida Ejaz4Steven Ford5Jamshed Iqbal6Centre of Excellence in Biotechnology Research, King Saud University, Riyadh 11451, Saudi Arabia; Research Chair for Biomedical Application of Nanomaterials. Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaResearch Chair for Biomedical Application of Nanomaterials. Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaCentre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, PakistanCentre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Department of Chemistry, Abbottabad University of Science and Technology, Abbottabad 22060, PakistanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia Univeristy of Bahawalpur, 63100, Punjab, Pakistan; Corresponding authors.Department of Pharmaceutical Sciences, Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UKCentre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Corresponding authors.Alzheimer's disease (AD) is one of the most debilitating forms of amyloidogenesis-induced dementia, and innovative, effective scaffolds are required for its treatment. Monoamine oxidase B (MAO-B) contributes to Alzheimer's by oxidizing monoamines and generating reactive oxygen species, thereby increasing oxidative stress and neuroinflammation. This makes MAO-B a promising therapeutic target to mitigate neuronal damage and slow disease progression. Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate-determining step in the production of a peptide, hence its inhibitors may play a crucial role in the treatment of Alzheimer's disease. Therefore, the successful inhibition of BACE1 by small compounds may be a viable strategy for the development of anti-AD drugs. In the current investigation, a small library of aminoquinazolinone-hydrazone derivatives underwent in-vitro and in-silico investigations. The anti-proliferative and antioxidant activities of aminoquinazolin-4(3H)-one derivatives (DH1-DH8) were evaluated, along with their cytotoxicity toward non-cancerous BHK-21 cells. Among the tested compounds, DH5 and DH7 exhibited the highest potency against cancer cells. Secondly, the study investigated their antioxidant potential using DPPH and ABTS assays. Notably, DH3, DH5, and DH8 demonstrated strong radical scavenging activity, with DH8 showing the highest ABTS scavenging potential. Structure-activity relationship (SAR) analysis revealed that electron-donating groups (-OH, -OMe) enhanced antioxidant and anti-proliferative activity, while hydrophobic (Cl) groups contributed to increased cytotoxicity against cancer cells. The newly synthesized compounds were also tested for BACE1 inhibition in-vitro using fluorescence resonance energy transfer (FRET) test methods. Among these compounds, the 2-nitrobenzylidene-containing compound (DH8) exhibited the strongest inhibitory action against BACE1, with an IC50 of 5.75 μM. Furthermore, during molecular docking studies, DH8 also demonstrated the maximum binding energy of −8.3 kcal/mol. These findings were further supported by molecular dynamics (MD) simulations, indicating the substantial stability of the protein-ligand complex. Additionally, in-silico ADME modeling was utilized to analyze the pharmacokinetic profile. Conclusively, the findings of the current study suggest hydrazineylquinazolinones as valuable scaffolds for the treatment of Alzheimer's disease by targeting BACE1.http://www.sciencedirect.com/science/article/pii/S2211715625003261Alzheimer's diseaseAminoquinazolinoneBACE1InhibitionMolecular dockingMD simulations |
| spellingShingle | Tajamul Hussain Salman Alrokayan Dilawar Hussain Khurram Shoaib Syeda Abida Ejaz Steven Ford Jamshed Iqbal Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease Results in Chemistry Alzheimer's disease Aminoquinazolinone BACE1 Inhibition Molecular docking MD simulations |
| title | Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease |
| title_full | Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease |
| title_fullStr | Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease |
| title_full_unstemmed | Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease |
| title_short | Aminoquinazolin-4(3H)-one derivatives as multitargeting therapeutics in Alzheimer's disease |
| title_sort | aminoquinazolin 4 3h one derivatives as multitargeting therapeutics in alzheimer s disease |
| topic | Alzheimer's disease Aminoquinazolinone BACE1 Inhibition Molecular docking MD simulations |
| url | http://www.sciencedirect.com/science/article/pii/S2211715625003261 |
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