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ORIGINAL RESEARCH article
Front. Med.
Sec. Precision Medicine
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1529845
This article is part of the Research Topic AI, Bioinformatics, and In Silico Based Biomarkers for the Diagnosis and Treatment of Neurodegenerative Diseases View all articles
Experimental and theoretical studies on structural changes in the microtubule affinityregulating kinase 4 (MARK4) protein induced by N-hetarenes: A new class of therapeutic candidates for Alzheimer's disease
Provisionally accepted
Ashanul Haque 1*
Khalaf M Alenezi 1
Mohd. Saeed Maulana Abdul Rasheed 2 Md. Ataur Rahman 3
Saleha Anwar 4
Shahzaib Ahamad 5
Dinesh Gupta 5- 1 Department of Chemistry, College of Sciences, University of Hail, Hail, Saudi Arabia
- 2 Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
- 3 New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
- 4 Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, Delhi, India
- 5 Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg 110067, New Delhi, India
Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder that progressively affects the cognitive function and memory of the affected person. Unfortunately, only a handful of effective prevention or treatment options are available today. Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine protein that plays a critical role in regulating microtubule dynamics and facilitating cell division. The dysregulated expression of MARK4 has been associated with a range of diseases, including AD.Methods: In this study, we synthesized a series of N-hetarenes via Pd(0)-catalysed Suzuki-Miyaura cross coupling reaction. All compounds were characterized using multi-spectroscopic techniques and evaluated for their activity against the MARK4 enzyme through ATPase inhibition assays. The experimental data was further supported by computational and quantum chemical calculations. We also computed the druglikeness, bioavailability, and toxicity (ADME/T) profiles of the compounds.Results: Six new 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides 5-10 were prepared in good yields. ATPase inhibition assay conducted on these compounds demonstrated IC50 values in micromolar range (5.35 ± 0.22 to 16.53 ± 1.71 μM). Among the tested compounds, 4-(6-(p-tolyl)pyrimidin-4yl)piperazine-1-carboximidamide (5; IC50 = 5.35 ± 0.22 μM) and 4- (6-(benzo[b]thiophen-2-yl)pyrimidin-4yl)piperazine-1-carboximidamide (9; IC50 = 6.68 ± 0.80 μM) showed the best activity. The binding constant (K), as determined by the fluorescence quenching assay was estimated to be 1.5 ± 0.51 × 10 5 M -1 for 5 and 1.14 ± 0.26 × 10 5 M -1 for 9. The results of molecular docking and MD simulation studies against MARK4 (PDB: 5ES1) indicated that compounds were able to bind the ATP binding pocket of the MARK4, leading to its stabilization. Additionally, ADME/T analysis revealed a high degree of drug-likeness of the compounds.In this study, we demonstrated that 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides) are a promising class of N-hetarenes for developing next-generation anti-AD drugs. These findings may provide valuable insights for future therapeutic strategies to address this complex neurodegenerative condition.
Keywords: Alzheimer's disease, Suzuki-Miyaura coupling, kinase inhibitor, pyrimidine derivatives, molecular docking, molecular dynamics
Received: 17 Nov 2024; Accepted: 18 Feb 2025.
Copyright: © 2025 Haque, Alenezi, Abdul 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 Sciences, University of Hail, Hail, Saudi Arabia
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