New hemiaminal ether dihydropyrimidinones as CK1/CK2 inhibitors targeting α-synuclein in Parkinson's disease
5 affiliations
- 1Department of Chemistry, University of Education Lahore Pakistan.
- 2Institute of Chemistry, University of Sargodha Sargodha Pakistan [email protected].
- 3Department of Pharmacology, Faculty of Pharmacy, Riphah International University Islamabad Pakistan.
- 4H.E.J Research Institute of Chemistry, ICCBS, University of Karachi Karachi Pakistan.
- 5WHO Sub-office, DHDC, Aziz Bhatti Shaheed Teaching Hospital Gujrat Pakistan.
Abstract
This study aimed to develop new dihdropyrimidones based inhibitors to slow Parkinson's disease progression by targeting casein kinase CK1, CK2, and α-synuclein receptors. A series of hemiaminal ether-functionalized DHPMs (3a-3h) was synthesized through late-stage alkoxymethylation of dihydropyrimidones in high yields (up to 92%) and characterized by NMR and mass spectrometry. Initial screening of the synthesized compounds (3a-3h) through molecular docking predicted strong binding to CK1 (PDB: 6RCG, up to -8.9 kcal mol⁻¹), CK2 (PDB: 3NSZ, up to -10.3 kcal mol⁻¹), and potential to inhibit α-synuclein (ASN) aggregation in both native (3Q25) and mutant forms (1XQ8). Normal mode analysis (NMA) examined the structural flexibility of mutant α-synuclein (1XQ8), while docking analysis identified potential binding regions (C1-C5), including interactions involving Ser129. In vitro studies suggested significant potential of the synthesized compounds through CK2 inhibition (IC₅₀: 9.3 to 13.5 µM), ADP-Glo™ kinase activity (IC₅₀: 1.69-21.45 µM), and nitric oxide scavenging activity to assess their potential antioxidant effects. Among the synthesized derivatives, (R)-menthyloxymethyl DHPM (3h) exhibited the highest activity, with IC₅₀ values of 9.3, 1.69, and 6.0 µM, respectively. Favorable ADMET and pharmacokinetic profiles supported the synthesized DHPM (3a-3h) derivatives as promising leads for inhibiting kinase activity (CK1/CK2) and preventing ASN aggregation in Parkinson's disease.
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BibTeX
@article{wakeel2026hemiaminal,
title = {{New hemiaminal ether dihydropyrimidinones as CK1/CK2 inhibitors targeting α-synuclein in Parkinson's disease}},
author = {Hamza Wakeel and Shanza Munir and Humaira Yasmeen Gondal and Zain Maqsood Cheema and Aleena Muskan and Imran Malik and Muhammad Nisar and Hina Siddiqui and Sadaf Khaliq Sultan},
journal = {RSC advances},
year = {2026},
month = nov,
doi = {10.1039/d6ra06901k},
url = {https://europepmc.org/article/PMC/PMC13725853},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - New hemiaminal ether dihydropyrimidinones as CK1/CK2 inhibitors targeting α-synuclein in Parkinson's disease
AU - Hamza Wakeel
AU - Shanza Munir
AU - Humaira Yasmeen Gondal
AU - Zain Maqsood Cheema
AU - Aleena Muskan
AU - Imran Malik
AU - Muhammad Nisar
AU - Hina Siddiqui
AU - Sadaf Khaliq Sultan
PY - 2026
DA - 2026/11/02
JO - RSC advances
DO - 10.1039/d6ra06901k
UR - https://europepmc.org/article/PMC/PMC13725853
AB - This study aimed to develop new dihdropyrimidones based inhibitors to slow Parkinson's disease progression by targeting casein kinase CK1, CK2, and α-synuclein receptors. A series of hemiaminal ether-functionalized DHPMs (3a-3h) was synthesized through late-stage alkoxymethylation of dihydropyrimidones in high yields (up to 92%) and characterized by NMR and mass spectrometry. Initial screening of the synthesized compounds (3a-3h) through molecular docking predicted strong binding to CK1 (PDB: 6RCG, up to -8.9 kcal mol⁻¹), CK2 (PDB: 3NSZ, up to -10.3 kcal mol⁻¹), and potential to inhibit α-synuclein (ASN) aggregation in both native (3Q25) and mutant forms (1XQ8). Normal mode analysis (NMA) examined the structural flexibility of mutant α-synuclein (1XQ8), while docking analysis identified potential binding regions (C1-C5), including interactions involving Ser129. In vitro studies suggested significant potential of the synthesized compounds through CK2 inhibition (IC₅₀: 9.3 to 13.5 µM), ADP-Glo™ kinase activity (IC₅₀: 1.69-21.45 µM), and nitric oxide scavenging activity to assess their potential antioxidant effects. Among the synthesized derivatives, (R)-menthyloxymethyl DHPM (3h) exhibited the highest activity, with IC₅₀ values of 9.3, 1.69, and 6.0 µM, respectively. Favorable ADMET and pharmacokinetic profiles supported the synthesized DHPM (3a-3h) derivatives as promising leads for inhibiting kinase activity (CK1/CK2) and preventing ASN aggregation in Parkinson's disease.
SN - 2046-2069
ER -