Dynamic stereochemistry of Topiramate (anticonvulsant drug) in solution: theoretical approaches and experimental validation

Topiramate, an antiepileptic drug, was synthesized with an improved protocol and identified by 1H NMR, 13C NMR, 1H–1H COSY, HMQC and HMBC spectrum. In parallel, density functional theory (DFT) using B3LYP functional and split-valance 6-311++G∗∗ basis set has been used to optimize the structures and conformers of Topiramate. Also experimental and theoretical methods have been used to correlate the dependencies of 1J and 2J involving 1H and 13C on the C1–C2 (ω) and C1–O1 (θ) torsion angles in the glycosidic part of Topiramate. New Karplus equations are proposed to assist in the structural interpretation of these couplings. Importantly, due to the sensitivity of some couplings, most notably 2JH1R,H1S, 2JC2,H1R and 2JC2,H1S values depend on both C–C (ω) and C–O (θ) torsion angles. Analyses of experimental coupling constants for protons on the pyranose ring of Topiramate indicate a twist boat structure for Topiramate in solution. In all calculations solvent effects were considered using a polarized continuum model (PCM).

Conformation and electronic structural details of Topiramate, an anticonvulsant drug, in solution have been studied using 2D NMR spectroscopy and QM calculations.Figure optionsDownload as PowerPoint slide