Structural Study of Selected Polyhalogenated Benzimidazoles (Protein Kinase CK2 Inhibitors) by Nuclear Quadrupole Double Resonance, X-ray, and Density Functional Theory

Abstract

Protein kinase CK2 inhibitors, polyhalogenated benzimidazoles, have been studied experimentally in solid state by NMR-NQR double resonance and X-ray and theoretically by the density functional theory (DFT). Six resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in each polyhalogenated benzimidazole molecule. The effects of prototropic annular tautomerism and polymorphism related to stable cluster formation due to intermolecular hydrogen bonding interactions on the (14)N NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism. The studies suggest that all polyhalogenobenzimidazoles are isostructural and can exhibit polymorphism and that (14)N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. NQDR and DFT results suggest the presence of the prototropic annular tautomerism 50:50, which is in a good agreement with the X-ray and (1)H NMR data.

Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

“…The NQR parameters obtained by B3LYP/6-311++G(d,p) assuming putative dimeric structure, Fig.1., were in a very good agreement with the experimental data [104]. Studies of isostructurality and annular 50:50 prototropic tautomerism of pentabromobenzimidazoles make another example of the successful prediction of crystalline structure performed by NQR and DFT/QTAIM combined [105]. On the basis of three known XRD structures of 4,5,6,7-tetraiodo-1H-benzimidazole, 4,6-dibromo-5,7-diiodo-1H-benzimidazole and 4,6-dichloro-5,7-diiodo-1H-benzimidazole the crystalline structures of a set of pentabromo-benzimidazoles have been proposed and the most stable polymorphic form (alpha) has been predicted.…”

“…An example are the studies of annular tautomerism of polyhalobenzimidazoles, Fig.4, [105]. NQDR and DFT results have suggested the presence of prototropic annular tautomerism 50:50, which is in a good agreement with the XRD and 1 H-NMR data.…”

“…A combination of experimental and theoretical techniques has certainly much to offer for the studies of drugs or potential drugs in early phases of drug research. Their capabilities in particular when applied to the known drugs, have been well documented in literature [92,99,101,104,105,148,[156][157][158][159][160][161][184][185][186][187][188][189]. Although in some fields the NMR or NQR are not competitive to IR, UV or XRD the examples of combined studies given above show that both techniques have a potential to elicit structural and physico-chemical information about a molecule of dug, target or the interaction drug-target.…”

“…The local potential energy density at BCPs indicated the following ordering of the intermolecular interactions according to increasing bond strength (E) : N1-H···N3 ~ N1-H···N3 < N1···X < X···Y (X, Y from the same ring) < X···Y (X, Y from the different rings). The pattern of intermolecular contacts has been found responsible for the specific crystal arrangement and the annular prototropism [105]. …”

A comparative study of the hydrogen-bonding patterns and prototropism in solid 2-thiocytosine (potential antileukemic agent) and cytosine, as studied by 1H-14N NQDR and QTAIM/ DFT

“…The presence of the “ordered” and “disordered” H-bonds in crystalline cytosine recently detected using the low-temperature FTIR [31] suggests that the possibility of formal proton migrations in cytosine requires further investigation. In our previous papers, we showed that 14 N NQDR and QTAIM/DFT combined studies are extremely helpful for interpreting the complicated NQR spectra and for studies of intermolecular interactions in the crystalline state [25, 32–34]. …”