Studies of molecular dynamics of thiazides by35Cl NQR spectroscopy and DFT calculation

Abstract

Abstraet. Molecular dynamics of three derivatives of 1,2,4-benzothiadiazine-l,l-dioxide, hydrochlorothiazide (HCTZ), althiazide (ATZ) and chlorotbiazide (CTZ), was studied by 35C1 nuclear quadrupole resonance (NQR) spectroscopy. The temperature dependence of the resonance frequency was analyzed within the 6 known standard models. The activation energies estimated from the temperature dependence of the 3~C1 NQR frequency assuming the Bayer model were 1.07, 2.35 and 2.76 kJ/mot for HCTZ, ATZ and CTZ respectivety, wbich confirms that HCTZ is Iess rigid than CTZ and ATZ is much more rigid than HCTZ, and suggests that the mechanism of relaxation is based on small amplitude librations. The characteristic temperatures estimated from the Bayer model, with that for CTZ (332.5 K) being much higher than for HCTZ (132.1 K), mean that the intermolecular interactions in CTZ are much stronger than in HCTZ, as suggested by the melting point of CTZ being higher than that for HCTZ. For ATZ the characteristic temperature (288 K) takes an intermediate value, which suggests that the intermolecular interactions in this compound are stronger than in HCTZ and weaker than in CTZ. A significant narrowing of the resonance 3~C1 NQR line observed for all these compounds at room temperature, relative to that at the liquid nitrogen temperature, suggests an averaging of dipolar interactions asa result of fast rotation of nonquadrupole nuclei in the vicinity of the quadrupote nuclei, when 2nv~r~ 87 1 (a rotation of the -NH z group in the direct neighborhood of the chlorine nuclei) or a change in the gradient o¡ with its value preserved (which is equivalent to rotation of the quadrupole nucleus CI). The influence of the rotations of the -NH~ and -CH2SCH2CH=CH z groups (ATZ) or -CHCI z group (TCTZ) on the 3~C1 NQR frequency was modelled by the B3LYP/6-31G" method. The frequencies of the libration vibrations calculated from the temperature dependence of the NQR resonance frequency were compared with experimental ones and those implied by the density functional theory, infrared and Raman spectra. For HCTZ the anomalies in the temperature dependence of the 35C1 NQR frequency, the lack of hysteresis and small but notable changes in the slope and the jump in the frequency observed at 253 K which does not exceed 0.05 MHz suggest a second-order phase transition at 253 K.

Structure-activity study of thiazides by magnetic resonance methods (NQR, NMR, EPR) and DFT calculations

“…The above conclusion is confirmed by a very good correlation between the available experimental IR of thiazides (CTZ and HCTZ) [18] with those calculated by DFT [14]. The short bond N(4)-C(10) 1.367 Å obtained for HCTZ agrees with that determined from X-ray diffraction 1.344 Å .…”

“….158 a Biological activity data from [3,4], complete set of experimental data [14][15][16][17][18][19][20]. b The lack of stable radical.…”

“…This paper is a continuation of the cycle of works [14][15][16][17][18][19][20] devoted to analysis of the effect of the intra and intermolecular interactions on the electronic structure of thiazides in solid phase by the resonance methods: nuclear quadrupole resonance-NQR, nuclear magnetic resonance-NMR, and electron paramagnetic resonance-EPR. In the earlier works analysis of the spectroscopic parameters such as quadrupole coupling constant (QCC), NQR, chemical shift (d), chemical shift anisotropy (CSA), asymmetry parameter (h), NMR and hyperfine coupling constant (A), EPR has been made, the possible structures and active sites have been proposed, the electronic effects (polarisation and delocalisation) estimated and the influence of irradiation on the electron density distribution in molecules established.…”

Electronic structure of thiazides studied by 35Cl‐NQR spectroscopy and DFT calculations

“…This apparent contradiction is explained by a comparison of the 35 Cl NQR spectra of the thiazides studied taken at liquid nitrogen and room temperature, Table 1. The dynamic effects (in thiazides mainly librations 26 ) can modify the substituent properties strongly enough that the substituent behaves like an electron acceptor instead of an electron donor. The analysis of the nitrogen or halogen bond populations is usually 27 -29 performed on the basis of NQR parameters obtained from the spectra recorded in liquid nitrogen, when it can be assumed that the molecular system is rigid and the zero vibrations can be neglected.…”

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

“…Interesting results have been obtained for hydrochlorothiazide (HCTZ), a diuretic drug applied to beat high blood pressure and heart failure. Among the DTA, NMR, NQR and XRD methods [171,172] the most sensitive to its phase transitions was NQR [172]. The anomalies in the temperature dependence of the 35 Cl NQR frequency for HCTZ, the change in the linewidth (being a result of an increase in the spin-lattice relaxation time), small but notable changes in the slope and the jump in frequency observed at 253 K, not exceeding 0.05 MHz, together with the lack of hysteresis (which distinguishes the first-and secondorder transitions) indicated a second-order transition.…”