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The RNA viruses SARS-CoV, SARS-CoV-2 and MERS-CoV encode the non-structural Nsp16 (2′-O-methyltransferase) that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the first ribonucleotide in mRNA. Recently, it has been found that breaking the bond between Nsp16 and SAM substrate results in the cessation of mRNA virus replication. To date, only a limited number of such inhibitors have been identified, which can be attributed to a lack of an effective "recipe". The aim of our study was to propose and verify a rapid and effective screening protocol dedicated to such purposes. We proposed four new indices describing structure-binding strength (structure–binding affinity, structure–hydrogen bonding, structure–steric and structure–protein–ligand indices) were then applied and shown to be extremely helpful in determining the degree of increase or decrease in binding affinity in response to a relatively small change in the ligand structure. After initial pre-selection, based on similarity to SAM, we limited the study to 967 compounds, so-called molecular chameleons. They were then docked in the Nsp16 protein pocket, and 10 candidate ligands were selected using the novel structure-binding affinity index. Subsequently the selected 10 candidate ligands and 8 known inhibitors and were docked to Nsp16 pockets from SARS-CoV-2, MERS-CoV and SARS-CoV. Based on the four new indices, the best ligands were selected and a new one was designed by tuning them. Finally, ADMET profiling and molecular dynamics simulations were performed for the best ligands. The new structure-binding strength indices can be successfully applied not only to screen and tune ligands, but also to determine the effectiveness of the ligand in response to changes in the target viral entity, which is particularly useful for assessing drug effectiveness in the case of alterations in viral proteins. The developed approach, the so-called chameleon strategy, has the capacity to introduce a novel universal paradigm to the field of drugs design, including RNA antivirals. [ABSTRACT FROM AUTHOR]

Cytarabine (Ara-C) is a synthetic isomer of cytidine that differs from cytidine and deoxycytidine only in the sugar. The use of arabinose instead of deoxyribose hinders the formation of phosphodiester linkages between pentoses, preventing the DNA chain from elongation and interrupting the DNA synthesis. The minor structural alteration (the inversion of hydroxyl at the 2′ positions of the sugar) leads to change of the biological activity from anti-depressant and DNA/RNA block builder to powerful anti-cancer. Our study aimed to determine the molecular nature of this phenomenon. Three 1H-14N NMR-NQR experimental techniques, followed by solid-state computational modelling (Quantum Theory of Atoms in Molecules, Reduced Density Gradient and 3D Hirshfeld surfaces), Quantitative Structure–Property Relationships, Spackman's Hirshfeld surfaces and Molecular Docking were used. Multifaceted analysis—combining experiments, computational modeling and molecular docking—provides deep insight into three-dimensional packing at the atomic and molecular levels, but is challenging. A spectrum with nine lines indicating the existence of three chemically inequivalent nitrogen sites in the Ara-C molecule was recorded, and the lines were assigned to them. The influence of the structural alteration on the NQR parameters was modeled in the solid (GGA/RPBE). For the comprehensive description of the nature of these interactions several factors were considered, including relative reactivity and the involvement of heavy atoms in various non-covalent interactions. The binding modes in the solid state and complex with dCK were investigated using the novel approaches: radial plots, heatmaps and root-mean-square deviation of the binding mode. We identified the intramolecular OH···O hydrogen bond as the key factor responsible for forcing the glycone conformation and strengthening NH···O bonds with Gln97, Asp133 and Ara128, and stacking with Phe137. The titular butterfly effect is associated with both the inversion and the presence of this intramolecular hydrogen bond. Our study elucidates the differences in the binding modes of Ara-C and cytidine, which should guide the design of more potent anti-cancer and anti-viral analogues. [ABSTRACT FROM AUTHOR]

Our study was motivated by the urgent need to develop or improve antivirals for effective therapy targeting RNA viruses. We hypothesized that analogues of favipiravir (FVP), an inhibitor of RNA-dependent RNA polymerase (RdRp), could provide more effective nucleic acid recognition and binding processes while reducing side effects such as cardiotoxicity, hepatotoxicity, teratogenicity, and embryotoxicity. We proposed a set of FVP analogues together with their forms of triphosphate as new SARS-CoV-2 RdRp inhibitors. The main aim of our study was to investigate changes in the mechanism and binding capacity resulting from these modifications. Using three different approaches, QTAIM, QSPR, and MD, the differences in the reactivity, toxicity, binding efficiency, and ability to be incorporated by RdRp were assessed. Two new quantum chemical reactivity descriptors, the relative electro-donating and electro-accepting power, were defined and successfully applied. Moreover, a new quantitative method for comparing binding modes was developed based on mathematical metrics and an atypical radar plot. These methods provide deep insight into the set of desirable properties responsible for inhibiting RdRp, allowing ligands to be conveniently screened. The proposed modification of the FVP structure seems to improve its binding ability and enhance the productive mode of binding. In particular, two of the FVP analogues (the trifluoro- and cyano-) bind very strongly to the RNA template, RNA primer, cofactors, and RdRp, and thus may constitute a very good alternative to FVP. [ABSTRACT FROM AUTHOR]

Paraxanthine (PX), a major metabolite of caffeine, a protective agent against Alzheimer's and Parkinson's disease, and a promising drug for the treatment of post-COVID 2019 anosmia and ageusia, has been studied in the solid state and protein–ligand complex. Partial disorder in PX, caused by the methyl group at the N(7) position, has been modelled and discussed. The relationship between the unusual structural disorder and the propensity to form a specific system of non-covalent bonds was analyzed. Three 1H-14N NMR-NQR (nuclear magnetic resonance–nuclear quadrupole resonance) experimental techniques were used, namely multiple frequency sweeps, Larmor frequency scanning, and the two-frequency irradiation, followed by solid-state computational modelling (density functional theory, supplemented by quantum theory of atoms in molecules, 3D Hirshfeld surfaces, and reduced density gradient), and molecular docking approaches. New quantitative methods for estimating changes in the global pattern of interactions under the influence of rotation of the methyl group in N(7) based on the Pompeiu–Hausdorff and Bhattacharayya metrics and the Wasserstein distance have been proposed and applied. A spectrum consisting of 12 lines, indicating the presence of 4 chemically inequivalent nitrogen sites in the PX molecule, was recorded, and the lines' assignment to particular sites was made. The influence of the methyl rotation on the eigenvalues and eigenvectors of the electric field gradient tensor, NQR parameters, and resonance line positions was modelled in the solid (GGA/RPBE, m-GGA/RSCAN) and cluster (Minnesota M062X hybrid). Three factors have been found to determine structural disorder in PX: larger crystal voids near the methyl at N(7) than at N(1) (opening the path for the disorder), hyperconjugation strongly affecting the density distribution in the five-membered ring, and the involvement of the methyl group at N(7) in many non-covalent bonds that intercept (capture) subsequent jumping protons. The Pompeiu–Hausdorff and Bhattacharayya metrics and the Wasserstein distance confirmed the changes in the distribution and strength of non-covalent interactions throughout the molecule as a result of methyl rotation. This effect is clearly visible regardless of the type of metric, and its order of magnitude is consistent with the modulation effect of the NQR spectra (experimental and calculated). Through molecular docking, it was discovered that the PX moiety in protein–ligand complexes adopt the same methyl group conformation at N(7) as in the solid state. It was found that the cooperation–competition between the C-H⋯O hydrogen bonds and C-H⋯H-C dispersion interactions is the crucial factor that impedes methyl rotation and induces structural disorder, as well as being an important factor in the formation of the protein–ligand complexes. [ABSTRACT FROM AUTHOR]

Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, FPV), an active pharmaceutical component of the drug discovered and registered in March 2014 in Japan under the name Avigan, with an indication for pandemic influenza, has been studied. The study of this compound was prompted by the idea that effective processes of recognition and binding of FPV to the nucleic acid are affected predominantly by the propensity to form intra- and intermolecular interactions. Three nuclear quadrupole resonance experimental techniques, namely 1H-14N cross-relaxation, multiple frequency sweeps, and two-frequency irradiation, followed by solid-state computational modelling (density functional theory supplemented by the quantum theory of atoms in molecules, 3D Hirshfeld Surfaces, and reduced density gradient) approaches were applied. The complete NQR spectrum consisting of nine lines indicating the presence of three chemically inequivalent nitrogen sites in the FPV molecule was detected, and the assignment of lines to particular sites was performed. The description of the nearest vicinity of all three nitrogen atoms was used to characterize the nature of the intermolecular interactions from the perspective of the local single atoms and to draw some conclusions on the nature of the interactions required for effective recognition and binding. The propensity to form the electrostatic N−H···O, N−H···N, and C−H···O intermolecular hydrogen bonds competitive with two intramolecular hydrogen bonds, strong O−H···O and very weak N−H···N, closing the 5-member ring and stiffening the structure, as well as π···π and F···F dispersive interactions, were analysed in detail. The hypothesis regarding the similarity of the interaction pattern in the solid and the RNA template was verified. It was discovered that the -NH2 group in the crystal participates in intermolecular hydrogen bonds N–H···N and N–H···O, in the precatalytic state only in N–H···O, while in the active state in N–H···N and N–H···O hydrogen bonds, which is of importance to link FVP to the RNA template. Our study elucidates the binding modes of FVP (in crystal, precatalytic, and active forms) in detail and should guide the design of more potent analogues targeting SARS-CoV-2. Strong direct binding of FVP-RTP to both the active site and cofactor discovered by us suggests a possible alternative, allosteric mechanism of FVP action, which may explain the scattering of the results of clinical trials or the synergistic effect observed in combined treatment against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

A series of new congeners, 1-[2-(1-adamantyl)ethyl]-1H-benzimidazole (AB) and 1-[2-(1-adamantyl)ethyl]-4,5,6,7-tetrahalogeno-1H-benzimidazole (Hal=Cl, Br, I; tClAB, tBrAB, tIAB), have been synthesized and studied. These novel multi-target ligands combine a benzimidazole ring known to show antitumor activity and an adamantyl moiety showing anti-influenza activity. Their crystal structures were determined by X-ray, while intermolecular interactions were studied using topological Bader's Quantum Theory of Atoms in Molecules, Hirshfeld Surfaces, CLP and PIXEL approaches. The newly synthesized compounds crystallize within two different space groups, P-1 (AB and tIAB) and P21/c (tClAB and tBrAB). A number of intramolecular hydrogen bonds, C−H⋯Hal (Hal=Cl, Br, I), were found in all halogen-containing congeners studied, but the intermolecular C−H⋯N hydrogen bond was detected only in AB and tIAB, while C−Hal⋯π only in tClAB and tBrAB. The interplay between C−H⋯N and C−H⋯Hal hydrogen bonds and a shift from the strong (C−H⋯Cl) to the very weak (C−H⋯I) attractive interactions upon Hal exchange, supplemented with Hal⋯Hal overlapping, determines the differences in the symmetry of crystalline packing and is crucial from the biological point of view. The hypothesis about the potential dual inhibitor role of the newly synthesized congeners was verified using molecular docking and the congeners were found to be pharmaceutically attractive as Human Casein Kinase 2, CK2, inhibitors, Membrane Matrix 2 Protein, M2, blockers and Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, inhibitors. The addition of adamantyl moiety seems to broaden and modify the therapeutic indices of the 4,5,6,7-tetrahalogeno-1H-benzimidazoles. [ABSTRACT FROM AUTHOR]

Serine/threonine protein kinases (CK2, PIM-1, RIO1) are constitutively active, highly conserved, pleiotropic, and multifunctional kinases, which control several signaling pathways and regulate many cellular functions, such as cell activity, survival, proliferation, and apoptosis. Over the past decades, they have gained increasing attention as potential therapeutic targets, ranging from various cancers and neurological, inflammation, and autoimmune disorders to viral diseases, including COVID-19. Despite the accumulation of a vast amount of experimental data, there is still no "recipe" that would facilitate the search for new effective kinase inhibitors. The aim of our study was to develop an effective screening method that would be useful for this purpose. A combination of Density Functional Theory calculations and molecular docking, supplemented with newly developed quantitative methods for the comparison of the binding modes, provided deep insight into the set of desirable properties responsible for their inhibition. The mathematical metrics helped assess the distance between the binding modes, while heatmaps revealed the locations in the ligand that should be modified according to binding site requirements. The Structure-Binding Affinity Index and Structural-Binding Affinity Landscape proposed in this paper helped to measure the extent to which binding affinity is gained or lost in response to a relatively small change in the ligand's structure. The combination of the physico-chemical profile with the aforementioned factors enabled the identification of both "dead" and "promising" search directions. Tests carried out on experimental data have validated and demonstrated the high efficiency of the proposed innovative approach. Our method for quantifying differences between the ligands and their binding capabilities holds promise for guiding future research on new anti-cancer agents. [ABSTRACT FROM AUTHOR]

The compound 3,3′-diindolylmethane (DIM) is a major in vivo product of digestion of indole-3-carbinol (I3C) (phytochemical from Brassicaceae family plants) and a main mediator of its chemopreventive and chemotherapeutic effects. In our previous paper, we have reported the impact of structural differences between DIM and I3C on their biological activity. In this paper, the coinfluence of two factors: polymorphism and temperature, on the topology, nature (Coulombic/polarization/dispersion/repulsion), and strength of interaction pattern in DIM are in our area of interest. Upon polymorph screening it has been found that DIM crystallizes in two polymorphic forms, form I (already known) and form II (newly obtained). differential scanning calorimetry indicated a slightly lower melting point for form I than for form II (436 versus 440 K) and the lack of phase transitions in both polymorphs. The crystal and molecular structures of both polymorphs have been determined as a function of temperature by single-crystal X-ray diffraction. The structure of polymorph I is monoclinic, space group C2/c, while polymorph II is orthorhombic, space group P212121. The DIM molecule adopts a twisted (both 1H-indole rings are aligned along the same direction, but they are twisted by about 61.5°) and a half-chair (the molecule is bent, and both 1H-indole rings make an angle of 68.9°) conformation, respectively, in forms I and II, which remain almost unaffected by temperature changes. Despite different relative orientations of both 1H-indole moieties in forms I and II, the differences in the interaction patterns revealed by quantum theory of atoms in molecules (QTAIM), reduced density gradient (RDS), Hirshfeld surfaces (3D HS), and two-dimensional molecular fingerprints (2D MF) are relatively small. The distribution of intermolecular interactions in the crystal of form II is by 5% less balanced than in that of form I. The Manhattan and Euclidean distances between the interactions do not exceed 3.76% and 2.21%, respectively, while the Bhattacharaya coefficient does not exceed 0.35. Solid state PDB/DPN calculations have revealed that in solid the twisted conformation of the molecule is less stable by 118.7 kJ/mol than that of the half-hair one, but despite this, polymorph I is more stable due to a greater number of weak intermolecular interactions stabilizing the crystalline packing. (In the gas phase the half-hair conformation of the molecule is less stable by 0.788 kJ/mol than the twisted one, which may be attributed to the existence of many weak interactions and crystal packing effects in the solid state, which are absent in the gas phase.) The key interaction stabilizing the twisted versus chair conformation and determining crystalline packing in both polymorphs of DIM is the NH···π one. The factor responsible for the locked conformation of DIM in both forms is the electrostatic potential complementarity of the regions of N-H···π, linking neighboring molecules, which permits easy overcoming of any repulsive interactions that may force rotation of the molecule. The commercial sample of DIM was found to contain approximately 50% of form I and 50% of form II. [ABSTRACT FROM AUTHOR]

Themechanism of molecular dynamics in the antibacterial/antifungalagent, triclosan (5-chloro-2-(2′,4′-dichlorophenoxy)-phenol),in solid state was studied by 1H NMR spectroscopy and periodicdensity functional theory (DFT) calculations. Temperature dependenciesof the proton spin–lattice relaxation time (T1)in the ranges 86–293 and 90–250 K (at 15 and 24.667MHz, respectively) and the second moment (M2) of the 1H NMR resonant line in the range 103–300 K were measured.Two minima in the temperature dependence of T1revealeda classical Arrhenius governed activation processes. The low temperatureshallow minimum T1(T)of 71 s at 115 K, 15 MHz, which shifts with frequency, was assignedto classical hindered jumps of hydroxyl group around OC axis and withrespect to a 5-chloro-2-phenol ring. The activation energy of thismotion estimated on the basis of the fit of the theoretical modelto the experimental points is 9.68 kJ/mol. The pointed high temperatureminimum T1(T) of 59 sat 190 K, 15 MHz, which also shifts with frequency, was assigned tothe small angle librations by Θlib= ± 9°between two positions of equilibrium differing in energy by 7.42 kJ/mol.The activation energy of this motion estimated on the basis of thefit of the theoretical model to the experimental points is 31.1 kJ/mol.Both motions result in a negligible reduction in the 1HNMR line second moment, thus the second moment delivers an irrelevantdescription of the molecular motions in triclosan. [ABSTRACT FROM AUTHOR]

Molecularrelaxation in antibacterial/antifungal agent: chloroxylenol(4-chloro-3,5-dimethylphenol, PCMX) in the solid state was studiedby the 1H NMR and quantum chemistry calculations. The temperaturedependencies of the proton spin–lattice relaxation time (T1) in the ranges 15–273 K (at 24.667MHz), 77–295 K (at 15 MHz), and 112–291 K at 90 MHzand the second moment (M2) of 1H NMR resonant line in the range 106–380 K were measured.The two minima in the temperature dependence of T1revealed two activation processes, whereas the M2dependence in the studied range was quiteflat and revealed the only significant reduction at 380 K. The lowtemperature part of T1(T) dependence indicated the occurrence of two processes characteristicof methyl bearing solids; the quantum mechanics governed incoherenttunneling (responsible for the low temperature flattening of T1) and the classical Arrhenius dependence governedhindered rotation (related to the wide low temperature minimum of0.066 s at 57 K, 24.667 MHz). The 2D potential energy surface obtainedusing DFT/B3LYP/6-311++G(2d,p) calculations revealed the inequivalenceof methyl groups and the lack of their interplay/coupling. The activationenergies of classical hindered rotation are 3.35 and 2.5 kJ/mol, whereastemperatures at which the proton tunneling Ttunfinally ceases are 52 and 63 K, for inequivalent methylgroups. Cp(T) required for the estimation of Ttunwas calculated purely theoretically on the basis of the Einsteinand Debye models of specific heat and 51 modes of atomic vibrations,4 internal rotations, and 3 torsions calculated by DFT. The −CH3motion (tunneling and classical) results in the reductionin the 1H NMR line second moment from 17.3 G2(rigid) to approximately 11.05 G2. The pointed high temperatureminimum T1(T) of 0.109s at 89 K, 24.667 MHz, which shifts with frequency, was assigned tosmall-angle libration jumps, by the Θ2= ±15°between two positions of equilibrium. The activation energy of thismotion estimated on the basis of the fit of the theoretical modelto the experimental points is 10.5 kJ/mol. The reduction in the 1H NMR line second moment assigned to this motion is much lower(due to order parameter s= 0.64) and equal to 1.6G2. The high temperature reduction from 9.6 G2to 0.9 G2at 380 K is a result of the phase transitionconnected with melting (385–389 K). [ABSTRACT FROM AUTHOR]

The application of combined 35Cl-NQR/X-ray/DFT/QTAIMmethods to study the temperature variation of anisotropic displacementparameters and ultralow frequency modes of anharmonic torsional vibrationsin the solid state is illustrated on the example of 2,4-dichloro-5-sulfamolybenzoicacid (lasamide, DSBA) which is a diuretic and an intermediate in thesynthesis of furosemide and thus its common impurity. The crystallographicstructure of lasamide is solved by X-ray diffraction and refined toa final R-factor of 3.06% at room temperature. Lasamideis found to crystallize in the triclinic space group P-1, with twoequivalent molecules in the unit cell a= 7.5984(3)Å, b= 8.3158(3) Å, c=8.6892(3) Å; α = 81.212(3)°, β = 73.799(3)°,γ = 67.599(3)°. Its molecules form symmetric dimers linkedby two short and linear intermolecular hydrogen bonds O–H···O(O–H···O = 2.648 Å and ∠OHO = 171.5°),which are further linked by weaker and longer intermolecular hydrogenbonds N–H···O (N–H···O= 2.965 Å and ∠NHO = 166.4°). Two 35Cl-NQRresonance frequencies, 36.899 and 37.129 MHz, revealed at room temperatureare assigned to chlorine sites at the orthoand parapositions, relative to the carboxyl functional group,respectively. The difference in C–Cl(1) and C–Cl(2)bond lengths only slightly affects the value of 35Cl-NQRfrequencies, which results mainly from chemical inequivalence of chlorineatoms but also involvement in different intermolecular interactionspattern. The smooth decrease in both 35Cl-NQR frequencieswith increasing temperature in the range of 77–300 K testifiesto the averaging of EFG tensor at each chlorine site due to anharmonictorsional vibrations. Lasamide is thermally stable; no temperature-inducedrelease of chlorine or decomposition of this compound is detected.The temperature dependence of ultralow frequency modes of anharmonicsmall-angle internal torsional vibrations averaging EFG tensor andmean square angle displacements at both chlorine sites is derivedfrom the 35Cl-NQR temperature dependence. The frequenciesof torsional vibrations higher for the parasitethan the orthosite are in good agreement with thoseobtained from thermal parameters obtained from X-ray studies. Themean square angle displacements are in good agreement with those estimatedfrom X-ray data with the use of the TLS model. The detailed DFT/QTAIManalysis suggests that the interplay between different hydrogen bondsin adjacent molecules forming dimers is responsible for the differencesin flexibility of the carboxyl and sulphonamide substituents as wellas both C–Cl(1) and C–Cl(2) bonds. Three ultralow wavenumbermodes of internal vibrations in Raman and IR spectra obtained at theB3LYP/6-311++G(d,p) level close to those obtained within the TLS modelsuggest that internal and external modes of vibrations are not wellseparated. [ABSTRACT FROM AUTHOR]

A series of new congeners, 1-[2-(1-adamantyl)ethyl]-1 H -benzimidazole (AB) and 1-[2-(1-adamantyl)ethyl]-4,5,6,7-tetrahalogeno-1 H -benzimidazole (Hal=Cl, Br, I; tClAB, tBrAB, tIAB), have been synthesized and studied. These novel multi-target ligands combine a benzimidazole ring known to show antitumor activity and an adamantyl moiety showing anti-influenza activity. Their crystal structures were determined by X-ray, while intermolecular interactions were studied using topological Bader's Quantum Theory of Atoms in Molecules, Hirshfeld Surfaces, CLP and PIXEL approaches. The newly synthesized compounds crystallize within two different space groups, P-1 (AB and tIAB) and P2 1 /c (tClAB and tBrAB). A number of intramolecular hydrogen bonds, C-H⋯Hal (Hal=Cl, Br, I), were found in all halogen-containing congeners studied, but the intermolecular C-H⋯N hydrogen bond was detected only in AB and tIAB, while C-Hal⋯π only in tClAB and tBrAB. The interplay between C-H⋯N and C-H⋯Hal hydrogen bonds and a shift from the strong (C-H⋯Cl) to the very weak (C-H⋯I) attractive interactions upon Hal exchange, supplemented with Hal⋯Hal overlapping, determines the differences in the symmetry of crystalline packing and is crucial from the biological point of view. The hypothesis about the potential dual inhibitor role of the newly synthesized congeners was verified using molecular docking and the congeners were found to be pharmaceutically attractive as Human Casein Kinase 2, CK2, inhibitors, Membrane Matrix 2 Protein, M2, blockers and Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, inhibitors. The addition of adamantyl moiety seems to broaden and modify the therapeutic indices of the 4,5,6,7-tetrahalogeno-1 H -benzimidazoles.

Three anhydrous methylxanthines: caffeine (1,3,7-trimethylxanthine; 1,3,7-trimethyl-1H-purine-2,6-(3H,7H)-dione) and its two metabolites theophylline (1,3-dimethylxanthine; 1,3-dimethyl-7H-purine-2,6-dione) and theobromine (3,7-dimethyl-xanthine; 3,7-dimethyl-7H-purine-2,6-dione), which reveal multifaceted therapeutic potential, have been studied experimentally in solid state by (1)H-(14)N NMR-NQR (nuclear magnetic resonance-nuclear quadrupole resonance) double resonance (NQDR). For each compound the complete NQR spectrum consisting of 12 lines was recorded. The multiplicity of NQR lines indicates the presence of a stable β form of anhydrous caffeine at 233 K and stable form II of anhydrous theobromine at 213 K. The assignment of signals detected in NQR experiment to particular nitrogen atoms was made on the basis of quantum chemistry calculations performed for monomer, cluster, and solid at the DFT/GGA/BLYP/DPD level. The shifts due to crystal packing interactions were evaluated, and the multiplets detected by NQR were assigned to N(9) in theobromine and N(1) and N(9) in caffeine. The ordering theobromine > theophylline > caffeine site and theophylline < theobromine < caffeine according to increasing electric field gradient (EFG) at the N(1) and N(7) sites, respectively, reflects the changes in biological activity profile of compounds from the methylxanthines series (different pharmacological effects). This difference is elucidated on the basis of the ability to form intra- and intermolecular interactions (hydrogen bonds and π···π stacking interactions). The introduction of methyl groups to xanthine restricts the ability of nitrogen atoms to participate in strong hydrogen bonds; as a result, the dominating effect shifts from hydrogen bond (theobromine) to π···π stacking (caffeine). Substantial differences in the intermolecular interactions in stable forms of methylxanthines differing in methylation (site or number) were analyzed within the Hirshfeld surface-based approach. The analysis of local environment of the nitrogen nucleus permitted drawing some conclusions on the nature of the interactions required for effective processes of recognition and binding of a given methylxanthine to A1-A(2A) receptor (target for caffeine in the brain). Although the interactions responsible for linking neighboring methylxanthines molecules in crystals and methylxanthines with targets in the human organism can differ significantly, the knowledge of the topology of interactions provides reliable preliminary information about the nature of this binding.

Allopurinol (1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one), the active pharmaceutical ingredient (API) of the drugs applied for the treatment of gout and tumor lysis syndrome, recently discovered to have multifaceted therapeutic potential, and hypoxanthine which is a naturally occurring purine have been studied experimentally in the solid state by (1)H-(14)N NMR-NQR double resonance. Twelve (14)N resonance frequencies have been detected at 295 K and assigned to two pairs of two kinds of nitrogen sites (-N═ and -NH) in each compound. The experimental results are supported by and interpreted with the help of quantum theory of atoms in molecules (QTAIM)/density functional theory (DFT) calculations. The factors, such as the substituent effect, in particular the shift of nitrogen from position 7 (as in hypoxanthine) to position 8 (as in allopurinol), hybridization, possible prototropic tautomerism, and the pattern of intermolecular bonding, have been taken into account in (1)H-(14)N NMR-NQR spectra interpretation. This study demonstrates the advantages of combining NQR, DFT/QTAIM, and Hirshfeld surface analysis to extract detailed information on electron density distribution and complex H-bonding networks in crystals of purinic type heterocycles, relevant in pharmacological processes. In the absence of X-ray data for xanthine, the NQR parameters supported by DFT/QTAIM calculations and Hirshfeld surface analysis were proved to be valuable tools for clarifying the details of crystalline packing and predicting an unsolved crystalline structure of xanthine. The influence of a decrease in purine ring conjugation level upon oxidation on the biological activity of allopurinol, a xanthine oxidase (XO) enzyme inhibitor, which blocks the conversion of hypoxanthine to xanthine and subsequently xanthine to uric acid, is also discussed.

The weak interaction patterns in 4,5,6,7-tetrahalogeno-1H-benzimidazoles, protein kinase CK2 inhibitors, in solid state are studied by the X-ray method and quantum chemistry calculations. The crystal structures of 4,5,6,7-tetrachloro- and 4,5,6,7-tetrabromo-1H-benzimidazole are determined by X-ray diffraction and refined to a final R-factor of 3.07 and 3.03%, respectively, at room temperature. The compound 4,5,6,7-tetrabromo-1H-benzimidazole, which crystallizes in the I41/a space group, is found to be isostructural with previously studied 4,5,6,7-tetraiodo-1H-benzimidazole in contrast to 4,5,6,7-tetrachloro-1H-benzimidazole, which crystallizes as triclinic P1̅ with 4 molecules in elementary unit. For 4,5,6,7-tetrachloro-1H-benzimidazole, differential scanning calorimetry (DSC) revealed a second order glassy phase transition at Tg = 95°/106° (heating/cooling), an indication of frozen disorder. The lack of 3D isostructurality found in all 4,5,6,7-tetrahalogeno-1H-benzimidazoles is elucidated on the basis of the intra- and intermolecular interactions (hydrogen bonding, van der Waals contacts, and C-H···π interactions). The topological Bader's Quantum Theory of Atoms in Molecules (QTAIM) and Spackman's Hirshfeld surface-based approaches reveal equilibration of electrostatic matching and dispersion van der Waals interactions between molecules consistent with the crystal site-symmetry. The weakening of van der Waals forces accompanied by increasing strength of the hydrogen bond (N-H···N) result in a decrease in the crystal site-symmetry and a change in molecular packing in the crystalline state. Crystal packing motifs were investigated with the aid of Hirshfeld surface fingerprint plots. The ordering 4,5,6,7-tetraiodo > 4,5,6,7-tetrabromo > 4,5,6,7-tetrachloro > 4,5,6,7-tetrafluoro reflects not only a decrease in crystal symmetry but also increase in chemical reactivity (electronic activation), which could explain some changes in biological activity of compounds from the 4,5,6,7-tetrahalogeno-1H-benzimidazole series. The ability of formation of a given type of bonds by 4,5,6,7-tetrahalogeno-1H-benzimidazole molecules is the same in the crystal and in CK2. Analysis of the interactions in the crystal permits drawing conclusions on the character (the way) of connections between a given 4,5,6,7-tetrahalogeno-1H-benzimidazole as a ligand with CK2 protein to make a protein-ligand complex.

Some thio- and aza-derivatives of natural nucleobases uracil and thymine: 2-thiouracil, 4-thiouracil, 6-methyl-2-thiouracil, 6-azauracil, and 6-aza-2-thiothymine have been studied experimentally in solid state by (1)H-(14)N NMR-NQR double resonance (NQDR) and theoretically by the Density Functional Theory (DFT)/Quantum Theory of Atoms in Molecules (QTAIM). The (14)N resonance frequencies have been measured at 173 and 295 K and assigned to particular nitrogen sites (-N═ and -NH-). The temperature factor has been found negligible. The changes in the molecular skeletons, electric charge distribution, intermolecular interactions pattern, and molecular aggregations caused by oxygen replacement with sulfur and carbon replacement with nitrogen are discussed in detail. Correlations between all the principal components of the (14)N quadrupole coupling tensor have been found helpful in the search for the experimental (14)N NQR frequencies, their assignment to a particular nitrogen positions and estimation of the strength of the inter- and intramolecular interactions. The variation in the NQR parameters have been mainly related to the variation in the population of π-electron orbital. For thiouracil derivatives a general trend is that the stronger the hydrogen bond is, the lower is the asymmetry parameter, while for thymine and 6-aza-2-thiotymine, the opposite relation holds. Differences in correlations of the principal components of the (14)N quadrupole coupling tensor at the amino and iminonitrogen positions in heterocyclic rings are discussed. The effect of C→H and C→N substitution at the amino nitrogen position and C→N substitution at the iminonitrogen position on the quadrupole coupling tensor is analyzed. This study also demonstrates the advantages of combining NQR and DFT/QTAIM to predict an unsolved crystalline structure of 4-thiouracil.