4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies
IntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of a person. Despite the significant research efforts, the ability to completely prevent or effectively treat AD and its related dementias remains limited. Protein kinase...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1517504/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832593926711672832 |
|---|---|
| author | Ashanul Haque Khalaf M. Alenezi Mohd. Saeed Maulana Abdul Rasheed Md. Ataur Rahman Saleha Anwar Shahzaib Ahamad Dinesh Gupta |
| author_facet | Ashanul Haque Khalaf M. Alenezi Mohd. Saeed Maulana Abdul Rasheed Md. Ataur Rahman Saleha Anwar Shahzaib Ahamad Dinesh Gupta |
| author_sort | Ashanul Haque |
| collection | DOAJ |
| description | IntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of a person. Despite the significant research efforts, the ability to completely prevent or effectively treat AD and its related dementias remains limited. Protein kinases are integral to AD pathology and represent promising targets for therapeutic intervention.MethodsA series of pyrimidine-based compounds 4-(4-(arylsulfonyl)piperazin-1-yl)-6-(thiophen-3-yl)pyrimidine derivatives (8-14) were synthesized and characterised. ATPase inhibition was carried out against the MARK4 enzyme. Molecular docking and molecular dynamics (MD) simulation at 500 ns was carried out against MARK4 (PDB: 5ES1). The drug-likeness feature and toxicity of the molecules were evaluated using QikProp and other tools.ResultsCompounds were synthesized following a multi-step approach and characterized using multi-nuclear magnetic resonance (1H/13C-NMR) and mass spectrometry. ATPase inhibition assay of the compounds against MARK4 showed an IC50 value in the micromolar (μM) range. The results of the docking studies were consistent with the in-vitro experiments and identified (9) and (14) as the candidates with the highest affinity towards MARK4. MD simulation further supported these results, showing that the binding of ligands stabilises the target protein.ConclusionUsing experimental and theoretical approaches, we demonstrated that the reported class of pyrimidine derivatives are an excellent starting point for developing the next-generation anti-AD drugs. |
| format | Article |
| id | doaj-art-5c3038879a564573b5a68335b289b562 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-5c3038879a564573b5a68335b289b5622025-01-20T07:19:43ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.151750415175044,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studiesAshanul Haque0Khalaf M. Alenezi1Mohd. Saeed Maulana Abdul Rasheed2Md. Ataur Rahman3Saleha Anwar4Shahzaib Ahamad5Dinesh Gupta6Department of Chemistry, College of Science, University of Hail, Ha’il, Saudi ArabiaDepartment of Chemistry, College of Science, University of Hail, Ha’il, Saudi ArabiaDepartment of Biology, College of Science, University of Hail, Ha’il, Saudi ArabiaChemistry Program, New York University Abu Dhabi (NYUAD), Abu Dhabi, United Arab EmiratesCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, IndiaTranslational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, IndiaTranslational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, IndiaIntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of a person. Despite the significant research efforts, the ability to completely prevent or effectively treat AD and its related dementias remains limited. Protein kinases are integral to AD pathology and represent promising targets for therapeutic intervention.MethodsA series of pyrimidine-based compounds 4-(4-(arylsulfonyl)piperazin-1-yl)-6-(thiophen-3-yl)pyrimidine derivatives (8-14) were synthesized and characterised. ATPase inhibition was carried out against the MARK4 enzyme. Molecular docking and molecular dynamics (MD) simulation at 500 ns was carried out against MARK4 (PDB: 5ES1). The drug-likeness feature and toxicity of the molecules were evaluated using QikProp and other tools.ResultsCompounds were synthesized following a multi-step approach and characterized using multi-nuclear magnetic resonance (1H/13C-NMR) and mass spectrometry. ATPase inhibition assay of the compounds against MARK4 showed an IC50 value in the micromolar (μM) range. The results of the docking studies were consistent with the in-vitro experiments and identified (9) and (14) as the candidates with the highest affinity towards MARK4. MD simulation further supported these results, showing that the binding of ligands stabilises the target protein.ConclusionUsing experimental and theoretical approaches, we demonstrated that the reported class of pyrimidine derivatives are an excellent starting point for developing the next-generation anti-AD drugs.https://www.frontiersin.org/articles/10.3389/fphar.2024.1517504/fullAlzheimer’s diseasekinase inhibitorsmark 4pyrimidinesynthesis |
| spellingShingle | Ashanul Haque Khalaf M. Alenezi Mohd. Saeed Maulana Abdul Rasheed Md. Ataur Rahman Saleha Anwar Shahzaib Ahamad Dinesh Gupta 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies Frontiers in Pharmacology Alzheimer’s disease kinase inhibitors mark 4 pyrimidine synthesis |
| title | 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies |
| title_full | 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies |
| title_fullStr | 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies |
| title_full_unstemmed | 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies |
| title_short | 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies |
| title_sort | 4 6 disubstituted pyrimidine based microtubule affinity regulating kinase 4 mark4 inhibitors synthesis characterization in vitro activity and in silico studies |
| topic | Alzheimer’s disease kinase inhibitors mark 4 pyrimidine synthesis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1517504/full |
| work_keys_str_mv | AT ashanulhaque 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies AT khalafmalenezi 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies AT mohdsaeedmaulanaabdulrasheed 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies AT mdataurrahman 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies AT salehaanwar 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies AT shahzaibahamad 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies AT dineshgupta 46disubstitutedpyrimidinebasedmicrotubuleaffinityregulatingkinase4mark4inhibitorssynthesischaracterizationinvitroactivityandinsilicostudies |