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Synthesis, molecular modeling, DFT studies, and EPR analysis of 1,4-dihydropyridines as potential calcium channel blockers
Date
2024-07-05
Author
KOÇAK ASLAN, EBRU
Lam, Kevin
Dengiz, Çağatay
Denzinger, Katrin
Dicle Erdamar, Isık Yesim
Huang, Sun
Zamponi, Gerald W.
Wolber, Gerhard
GÜNDÜZ, MİYASE GÖZDE
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1,4-Dihydropyridines (DHPs) are widely recognized as a highly effective class of L-type calcium channel blockers that offer significant therapeutic potential in managing cardiovascular conditions. Furthermore, their ability to target other types of calcium channels makes DHPs attractive candidates for therapeutic applications in neurological and psychiatric disorders. Close examination of the chemical structures of approved DHP-based antihypertensive drugs with a history of over forty years in the market reveals that the C-4 position is the least altered part of this privileged ring system. In the present study, we focused on this position and synthesized two novel compounds (DB1 and DB2) by carrying out chemical modifications on suitable positions of the main scaffold of DA1 (isobutyl 4-(benzo[d][1,3]dioxol-5-yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate) that was previously identified as a DHP-based effective and selective inhibitor of T-type (Cav3.2) over L-type (Cav1.2) calcium channel. Based on whole-cell patch-clamp analysis on Cav1.2 and Cav3.2, DB1 with bromine group on the benzodioxole ring appeared to be a more effective and selective inhibitor of Cav3.2 compared to DB2 with nitro at the same locus. Molecular docking and molecular dynamics (MD) simulations were performed to investigate the binding mode of both DB1 isomers to Cav3.2. Furthermore, density functional theory (DFT) methods were employed to obtain information regarding the stability of the molecules by computing various parameters, such as electric dipole moment, band gap, electronegativity, and global chemical hardness-softness, related to their charge-transfer characteristics. According to DFT studies, DB1 also appeared to be chemically more stable than DB2. Finally, ionizing radiation-induced free radicals of gamma-irradiated DB1 and DB2 in powder form were examined utilizing the electron paramagnetic resonance (EPR) technique and the obtained data demonstrated that radiation sterilization is suitable for the dosage forms including DB1 and DB2.
Subject Keywords
3D pharmacophore
,
Benzodioxole
,
Chemical stability
,
Dihydropyridine
,
Hexahydroquinoline
,
Molecular dynamics
URI
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85188795259&origin=inward
https://hdl.handle.net/11511/109347
Journal
Journal of Molecular Structure
DOI
https://doi.org/10.1016/j.molstruc.2024.137983
Collections
Department of Chemistry, Article
Citation Formats
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MLA
BibTeX
E. KOÇAK ASLAN et al., “Synthesis, molecular modeling, DFT studies, and EPR analysis of 1,4-dihydropyridines as potential calcium channel blockers,”
Journal of Molecular Structure
, vol. 1307, pp. 0–0, 2024, Accessed: 00, 2024. [Online]. Available: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85188795259&origin=inward.