Browsing by Author "Jai Prakash Yadav"

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Atomic-Scale Resolution Insights into Structural and Dynamic Differences between Ofloxacin and Levofloxacin
(American Chemical Society, 2023) Bijay Laxmi Pradhan; Jai Prakash Yadav; Lekhan Lodhi; Prince Sen; Krishna Kishor Dey; Manasi Ghosh
This study employs advanced solid-state NMR techniques to investigate the atomic-level structure and dynamics of two enantiomers: ofloxacin and levofloxacin. The investigation focuses on critical attributes, such as the principal components of the chemical shift anisotropy (CSA) tensor, the spatial proximity of 1H and 13C nuclei, and site-specific 13C spin-lattice relaxation time, to reveal the local electronic environment surrounding specific nuclei. Levofloxacin, the levo-isomer of ofloxacin, exhibits higher antibiotic efficacy than its counterpart, and the dissimilarities in the CSA parameters indicate significant differences in the local electronic configuration and nuclear spin dynamics between the two enantiomers. Additionally, the study employs the 1H-13C frequency-switched Lee-Goldburg heteronuclear correlation (FSLGHETCOR) experiment to identify the presence of heteronuclear correlations between specific nuclei (C15 and H7 nuclei and C13 and H12 nuclei) in ofloxacin but not in levofloxacin. These observations offer insights into the link between bioavailability and nuclear spin dynamics, underscoring the significance of NMR crystallography approaches in advanced drug design. © 2023 The Authors. Published by American Chemical Society.
Investigation of the Influence of Various Functional Groups on the Dynamics of Glucocorticoids
(American Chemical Society, 2022) Jai Prakash Yadav; Lekhan Lodhi; Tamseel Fatma; Krishna Kishor Dey; Manasi Ghosh
The basic configuration of glucocorticoid consists of four-fused rings associated with one cyclohexadienone ring, two cyclohexane rings, and one cyclopentane ring. The ways the structure and dynamics of five glucocorticoids (prednisone, prednisolone, prednisolone acetate, methylprednisolone, and methylprednisolone acetate) are altered because of the substitution of various functional groups with these four-fused rings are studied thoroughly by applying sophisticated solid-state nuclear magnetic resonance (NMR) methodologies. The biological activities of these glucocorticoids are also changed because of the attachment of various functional groups with these four-fused rings. The substitution of the hydroxyl group (with the C11 atom of the cyclohexane ring) in place of the keto group enhances the potential of the glucocorticoid to cross the cellular membrane. As a result, the bioavailability of prednisolone (the hydroxyl group is attached with the C11 atom of the cyclohexane ring) is increased compared to prednisone (the keto group is attached with the C11 atom of cyclohexane rings). Another notable point is that the spin-lattice relaxation rate at crystallographically distinct carbon nuclei sites of prednisolone is increased compared to that of the prednisone, which implies that the motional degrees of freedom of glucocorticoid is increased because of the substitution of the hydroxyl group in place of the keto group of the cyclohexane ring. The attachment of the methyl group with the C6 atom of cyclohexane rings further reduces the spin-lattice relaxation time at crystallographically distinct carbon nuclei sites of glucocorticoid and its bioactivity is also increased. By comparing the spin-lattice relaxation time and the local correlation time at crystallographically different carbon nuclei sites of three steroids prednisone, prednisolone, and methylprednisolone, it is observed that both the spin-lattice relaxation time and the local correlation time gradually decrease at each crystallographically distinct carbon nuclei sites when we move from prednisone to prednisolone to methyl-prednisolone. On the other hand, if we compare the same for prednisolone, prednisolone acetate, and methylprednisolone acetate, then we also observe that both the spin-lattice relaxation time and the local-correlation time gradually decrease from prednisolone to prednisolone acetate to methylprednisolone acetate for all chemically different carbon nuclei. It is also noticeable that both the spin-lattice relaxation time and the local-correlation time gradually decrease from prednisone to prednisolone to prednisolone acetate to methylprednisolone to methylprednisolone acetate for most of the carbon nuclei sites. From in silico analysis, it is also revealed that the bioavailability and efficacy of the glucocorticoid increase from prednisone to prednisolone to prednisolone acetate to methylprednisolone to methylprednisolone acetate. Hence, it can be concluded that the biological activity and the motional degrees of freedom of the glucocorticoids are highly correlated. These types of studies provide a clear picture of the structure-activity relationship of the drug molecules, which will enlighten the path of developing highly potent glucocorticoids with minimum side effects. Another important aspect of these types of studies is to provide information about the electronics configuration and nuclear spin dynamics at crystallographically different carbon nuclei sites of five glucocorticoids, which will enrich the field of "NMR crystallography". © 2022 American Chemical Society. All rights reserved.
NMR Crystallographic Approach to Study the Variation of the Dynamics of Quinine and Its Quasienantiomer Quinidine
(American Chemical Society, 2022) Lekhan Lodhi; Jai Prakash Yadav; Toshio Yamazaki; Nghia Tuan Duong; Srinivasa L. Poojary; Krishna Kishor Dey; Yusuke Nishiyama; Manasi Ghosh
The structure and dynamics of quinine and its quasienantiomer quinidine were studied at the atomic resolution by measuring the chemical shift anisotropy (CSA) tensor and site-specific spin-lattice relaxation time. For quinine, there are three crystallographically independent molecules "a", "b", and "c"in an asymmetric unit since its 13C CP-MAS SSNMR spectrum features three distinct resonance peaks for certain carbon nuclei. The 13C assignments are fulfilled by DFT calculations. The experimental 13C isotropic chemical shifts well match the calculated values. These variations of isotropic chemical shift for three independent molecules are also observed by two-dimensional 13C-1H heteronuclear correlation spectroscopy (HETCOR) of quinine. The spin-lattice relaxation time, and the principal components of CSA parameters are also varied substantially for certain carbon nuclei of "a", "b", and "c"molecules. For quinidine, its 13C CP-MAS SSNMR spectrum is remarkably different from that of quinine despite, their almost identical solution NMR spectra. Furthermore, the remarkable change in the structure and dynamics of quasienantiomers are also observed including the steric effect of the substituent vinyl group, the variation of helical motifs, and the variation of the strength of the intermolecular hydrogen bonds. The variation of the structure and dynamics of quasienantiomers are thoroughly studied by solid-state NMR measurements. These types of studies will enrich the field of NMR crystallography. © 2022 American Chemical Society.