RESUMEN
Stability of the antihypertensive drug nifedipine (NIF) has been studied experimentally in solid state by (1)H-(14)N NMR-NQR double resonance (NQDR) and theoretically by the Density Functional Theory (DFT). Photodegradation of NIF to its metabolite in vivo nitrosonifedipine, NO-NIF (antioxidative agent) upon long term daylight exposure was detected and the changes in the molecular structure of NIF were analysed. The photoconversion of NIF to NO-NIF in solid was found to be accompanied with the electron density redistribution at nitrogen sites (NH to N and NO(2) to NO) and proved to be successfully detected with identification of photoproducts by (1)H-(14)N NQDR and DFT methods. The increase in the e(2)qQ/h and η describing EFG tendency towards non-spherical symmetry was significantly greater upon the reduction of NO(2) site than upon hydrogen abstraction from NH site. The level of sensitivity of detection of the photodegradation product was about 1% of the original sample. The Quantum Theory of Atoms in Molecules (QTAIM) analysis has been found useful in predicting photoreactive sites in the molecules and finding the explanation of differences in reactivity between parent NIF and its photoproduct NO-NIF. Using NIF as a model, this study demonstrates the suitability of NQDR supported by DFT for non-destructive determination of the photodegradation products in solid state.
Asunto(s)
Antihipertensivos/química , Antioxidantes/química , Nifedipino/análogos & derivados , Nifedipino/química , Compuestos Nitrosos/química , Antihipertensivos/metabolismo , Antioxidantes/metabolismo , Hidrógeno/química , Espectroscopía de Resonancia Magnética/métodos , Nifedipino/metabolismo , Nitrógeno/química , Compuestos Nitrosos/metabolismo , Fotólisis , Teoría CuánticaRESUMEN
Two antibacterial and antifungal agents, chloroxylenol (4-chloro-3,5-dimethyl-phenol) and triclosan (5-chloro-2-(2',4'-dichlorophenoxy)-phenol), were studied experimentally in solid state with an X-ray, (35)Cl-nuclear quadrupole resonance (NQR) and (17)O-nuclear quadrupole double resonance (NQDR) spectroscopies and, theoretically, with the density functional theory/quantum theory of atoms in molecules (DFT/QTAIM). The crystallographic structure of triclosan, which crystallises in space group P31 with one molecule in the asymmetric unit [a = 12.64100(10), b = 12.64100(10), c = 6.71630(10) Å], was solved with an X-ray and refined to a final R-factor of 2.81% at room temperature. The NQR frequencies of (35)Cl and (17)O were detected with the help of the density functional theory (DFT) assigned to particular chlorine and oxygen sites in the molecules of both compounds. The NQR frequencies at (35)Cl sites in chloroxylenol and triclosan were found to be more differentiated than frequencies at the (17)O site. The former better describes the substituent withdrawing effects connected to π-electron delocalization within the benzene rings and the influence of temperature; whereas, those at the (17)O site provide more information on O-H bond and intermolecular interactions pattern. The conformation adopted by diphenyl ether of triclosan in solid state was found to be typical of diphenyl ethers, but the opposite to those adopted when it was bound to different inhibitors. According to an X-ray study, temperature had no effect on the conformation of the diphenyl ring of triclosan, which was the same at 90 K and at room temperature (RT). The scattering of NQR frequencies reproduced by the DFT under assumption of the X-ray data at 90 K and RT is found to be a good indicator of the quality of resolution of the crystallographic structure.
Asunto(s)
Antibacterianos/química , Antifúngicos/química , Electrones , Resonancia Magnética Nuclear Biomolecular/métodos , Triclosán/química , Xilenos/química , Cloro , Cristalografía por Rayos X , Isótopos , Conformación Molecular , Isótopos de Oxígeno , Teoría Cuántica , TemperaturaRESUMEN
Isothioureas, inhibitors of nitric oxide synthases, have been studied experimentally in solid state by nuclear quadrupole double resonance (NQDR) and X-ray methods and theoretically by the quantum theory of atoms in molecules/density functional theory. Resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in each molecule. The crystal packings of (S)-3,4-dichlorobenzyl-N-methylisothiouronium chloride with the disordered chlorine positions in benzene ring and (S)-butyloisothiouronium bromide have been resolved in X-ray diffraction studies. (14)N NQDR spectra have been found good indicators of isomer type and strength of intra- or intermolecular N-H···X (X = Cl, Br) interactions. From among all salts studied, only for (S)-2,3,4,5,6-pentabromobenzylisothiouronium chloride are both nitrogen sites equivalent, which has been explained by the slow exchange. This unique structural feature can be a key factor in the high biological activity of (S)-2,3,4,5,6-pentabromobenzylisothiouronium salts.
Asunto(s)
Óxido Nítrico Sintasa/antagonistas & inhibidores , Teoría Cuántica , Tiourea/química , Bromuros/química , Cloruros/química , Isomerismo , Modelos Moleculares , Óxido Nítrico Sintasa/química , Tiourea/farmacologíaRESUMEN
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.
Asunto(s)
Bencimidazoles/química , Simulación por Computador , Modelos Químicos , Inhibidores de Proteínas Quinasas/química , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Teoría CuánticaRESUMEN
A chemotherapeutic drug 6-thioguanine (2-amino-1,7-dihydro-6H-purine-6-thione, 6-TG) has been studied experimentally in the solid state by NMR-NQR double resonance and theoretically by the density functional theory. Fourteen resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in the 6-TG molecule. A valid assignment of NQR frequencies for 6-mercaptopurine (6-MP) has been proposed. The effects of molecular aggregations, related to intermolecular hydrogen bonding and stacking pi-pi interactions on the NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism for 6-TG and 6-mercaptopurine (6-MP). The so-called global reactivity descriptors have been calculated to compare the properties of molecules of 6-TG and 6-MP, to check the effect of -NH(2) group as well as to identify the differences in crystal packing.
Asunto(s)
Simulación por Computador , Mercaptopurina/química , Modelos Químicos , Tioguanina/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética/métodosRESUMEN
The main idea of this work was to give an overview of the NQR capabilities in the search for a correlation between electronic structure and biological activity of certain compounds, mainly drugs. A correlation between the parameters characterising biological activity and the NQR spectral parameters describing chemical properties of a given compound, permits drawing conclusions on biological effectiveness of compounds from a certain group. The quadrupole coupling constants, which are very well correlated with atomic charges, can be treated as descriptors in QSAR. The information inferred from NQR study on local electron density distribution together with analysis of charge distribution, provides excellent means for determination of reactive sites and hence, can indicate possible promising directions to be followed in drugs design.
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Preparaciones Farmacéuticas/química , Animales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Electrones , Humanos , Preparaciones Farmacéuticas/análisis , Farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
The paper presents a comprehensive analysis of the relationship between the electronic structure of thiazides and their biological activity. The compounds of interest were studied in solid state by the resonance methods nuclear quadrupole resonance (NQR), nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) and quantum chemistry (ab inito and DFT) methods. Detailed parallel analysis of the spectroscopic parameters such as quadrupole coupling constant (QCC) NQR chemical shift (delta), chemical shift anisotropy (CSA), asymmetry parameter (eta), NMR and hyperfine coupling constant (A), EPR was performed and the electronic effects (polarisation and delocalisation) were revealed and compared. Biological activity of thiazides has been found to depend on many factors, but mainly on the physico-chemical properties whose assessment was possible on the basis of electron density determination in the molecules performed by experimental and theoretical methods.
Asunto(s)
Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Espectroscopía de Resonancia por Spin del Electrón , Espectroscopía de Resonancia Magnética , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A nuclear quadrupole resonance (NQR) study of the electronic structure of bridging halogen atoms in dimers of transition and non-transition metal halides has been performed. An explanation of the differences in the NQR frequencies for transition and non-transition metal halides is proposed. The population of the bridging halogen atom orbitals and the metal-halogen bond lengths have been estimated by the AM1 method. The aim of this paper was to obtain a relationship describing the lengths of the metal-halogen bonds.