A Description of the Local Structure and Dynamics of Ketoconazole Molecule by Solid-State NMR Measurements and DFT Calculations: Proposition for NMR Crystallography

An azole class antifungal agent, ketoconazole, is widely used in the treatment of mucosal fungal infections that arise due to AIDS immunosuppression, organ transplantation, and cancer chemotherapy. The structure and dynamics of various molecular moieties of ketoconazole are thoroughly studied by measuring chemical shift anisotropy tensor and site-specific spin-lattice relaxation time. The local correlation time at crystallographically different carbon nuclei sites is also calculated. The chemical shift anisotropy (CSA) parameters at the crystallographically distinct sites of ketoconazole are determined by the two-dimensional phase-adjusted spinning sideband (2D PASS) cross-polarization magic angle spinning (CP-MAS) solid-state NMR experiment. The site-specific spin-lattice relaxation time is measured by the method outlined by Torchia (T1CP). The values of the principal components of CSA parameters extracted by the 2DPASS CP-MAS ssNMR experiment are supported by density functional theory (DFT) calculations. The CSA parameters are high for those carbon nuclei, whose spin-lattice relaxation rate is slow, and it is low for those carbon nuclei whose spin-lattice relaxation rate is fast. It suggests that the spin-lattice relaxation mechanism is mainly governed by chemical-shift anisotropy interaction for these carbon nuclei. A huge variation of the spin-lattice relaxation time and the local correlation time are observed for numerous carbon nuclei that reside on the side-chain of the molecule. The spin-lattice relaxation time varies from 500 s to 8 s, and the order of the local correlation time varies from 10-4 s to 10-7 s. These types of studies in which the chemical shift anisotropy (CSA) parameters and spin-lattice relaxation time provide information about the electronic configuration and the spin dynamics at the various crystallographic locations of the drug molecule will enrich the field "NMR crystallography." It will also help to develop the strategies for the administration of antifungal drugs by providing information about the structure and dynamics of various parts of the drug molecule.