Experimental and theoretical studies on structural changes in the microtubule affinity-regulating kinase 4 (MARK4) protein induced by N-hetarenes: a new class of therapeutic candidates for Alzheimer’s disease DOI Creative Commons
Ashanul Haque, Khalaf M. Alenezi,

Mohd. Saeed Maulana Abdul Rasheed

et al.

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: March 19, 2025

Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively affects the cognitive function and memory of affected person. Unfortunately, only handful effective prevention or treatment options are available today. Microtubule affinity-regulating kinase 4 (MARK4) serine/threonine protein plays critical role in regulating microtubule dynamics facilitating cell division. The dysregulated expression MARK4 has been associated with range diseases, including AD. Methods In this study, we synthesized series N -hetarenes via Pd(0)-catalyzed Suzuki-Miyaura cross coupling reaction. All compounds were characterized using multi-spectroscopic techniques evaluated for their activity against enzyme through ATPase inhibition assays. experimental data was further supported by computational quantum chemical calculations. We also computed drug-likeness, bioavailability, toxicity (ADME/T) profiles compounds. Results Six new 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides 5−10 prepared good yields. assay conducted on these demonstrated IC 50 values micromolar (5.35 ± 0.22 to 16.53 1.71 μM). Among tested compounds, 4-(6-( p -tolyl)pyrimidin-4-yl)piperazine-1-carboximidamide ( 5 ; = 5.35 μM) 4-(6-(benzo[ b ]thiophen-2-yl)pyrimidin-4-yl)piperazine-1-carboximidamide 9 6.68 0.80 showed best activity. binding constant K ), as determined fluorescence quenching estimated be 1.5 0.51 × 10 M −1 1.14 0.26 . results molecular docking MD simulation studies (PDB: 5ES1) indicated able bind ATP pocket MARK4, leading its stabilization. Additionally, ADME/T analysis revealed high degree drug-likeness Conclusion 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides) promising class developing next-generation anti-AD drugs. reported inhibited in-vitro at concentration targeting ATP-binding pocket. These findings provide valuable insights future drug design.

Language: Английский

Experimental and theoretical studies on structural changes in the microtubule affinity-regulating kinase 4 (MARK4) protein induced by N-hetarenes: a new class of therapeutic candidates for Alzheimer’s disease DOI Creative Commons
Ashanul Haque, Khalaf M. Alenezi,

Mohd. Saeed Maulana Abdul Rasheed

et al.

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: March 19, 2025

Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively affects the cognitive function and memory of affected person. Unfortunately, only handful effective prevention or treatment options are available today. Microtubule affinity-regulating kinase 4 (MARK4) serine/threonine protein plays critical role in regulating microtubule dynamics facilitating cell division. The dysregulated expression MARK4 has been associated with range diseases, including AD. Methods In this study, we synthesized series N -hetarenes via Pd(0)-catalyzed Suzuki-Miyaura cross coupling reaction. All compounds were characterized using multi-spectroscopic techniques evaluated for their activity against enzyme through ATPase inhibition assays. experimental data was further supported by computational quantum chemical calculations. We also computed drug-likeness, bioavailability, toxicity (ADME/T) profiles compounds. Results Six new 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides 5−10 prepared good yields. assay conducted on these demonstrated IC 50 values micromolar (5.35 ± 0.22 to 16.53 1.71 μM). Among tested compounds, 4-(6-( p -tolyl)pyrimidin-4-yl)piperazine-1-carboximidamide ( 5 ; = 5.35 μM) 4-(6-(benzo[ b ]thiophen-2-yl)pyrimidin-4-yl)piperazine-1-carboximidamide 9 6.68 0.80 showed best activity. binding constant K ), as determined fluorescence quenching estimated be 1.5 0.51 × 10 M −1 1.14 0.26 . results molecular docking MD simulation studies (PDB: 5ES1) indicated able bind ATP pocket MARK4, leading its stabilization. Additionally, ADME/T analysis revealed high degree drug-likeness Conclusion 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides) promising class developing next-generation anti-AD drugs. reported inhibited in-vitro at concentration targeting ATP-binding pocket. These findings provide valuable insights future drug design.

Language: Английский

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