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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1517504

4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: Synthesis, characterization, in-vitro activity and in-silico studies

Provisionally accepted
Ashanul Haque Ashanul Haque 1*Khalaf M Alenezi Khalaf M Alenezi 1Mohd. Saeed Maulana Abdul Rasheed Mohd. Saeed Maulana Abdul Rasheed 2Md. Ataur Rahman Md. Ataur Rahman 3Saleha Anwar Saleha Anwar 4Shahzaib Ahamad Shahzaib Ahamad 5Dinesh Gupta Dinesh Gupta 5
  • 1 Department of Chemistry, College of Science, University of Hail, Ha'il, Saudi Arabia
  • 2 Department of Biology, College of Science, University of Hail, Ha'il, Saudi Arabia
  • 3 New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
  • 4 Centre for Interdisciplinary Research in Basic Sciences, New Delhi, India, Jamia Millia Islamia, New Delhi, National Capital Territory of Delhi, India
  • 5 Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg 110067, International Centre for Genetic Engineering and Biotechnology (India), New Delhi, Delhi, India

The final, formatted version of the article will be published soon.

    Introduction: Alzheimer'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.Methods: A series of pyrimidine-based compounds 4-(4-arylpiperazin-1-yl)-6-(thiophen-3yl)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.Results: Compounds were synthesized following a multi-step approach and characterized using multi-nuclear magnetic resonance ( 1 H/ 13 C-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.Conclusions: Using 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.

    Keywords: Alzheimer's disease, kinase inhibitors, Mark 4, Pyrimidine, Synthesis

    Received: 29 Oct 2024; Accepted: 17 Dec 2024.

    Copyright: © 2024 Haque, Alenezi, Rasheed, Rahman, Anwar, Ahamad and Gupta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ashanul Haque, Department of Chemistry, College of Science, University of Hail, Ha'il, Saudi Arabia

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.