S(-) and R(+) species derived from antihistaminic promethazine agent: structural and vibrational studies

Abstract

Structural and vibrational properties of free base, cationic and hydrochloride species derived from both S(-) and R(+) enantiomers of antihistaminic promethazine (PTZ) agent have been theoretically evaluated in gas phase and in aqueous solution by using the hybrid B3LYP/6-31G* calculations. The initial structures of S(-) and R(+) enantiomers of hydrochloride PTZ were those polymorphic forms 1 and 2 experimentally determined by X-ray diffraction. Here, all structures in aqueous solution were optimized at the same level of theory by using the polarized continuum (PCM) and the universal solvation model. As was experimentally reported, variations in the unit cell lead to slight energy, density, and melting point differences between the two forms but, this behavior is not carried through in isotropic condition, like in solution with non-chiral solvents. Hence, the N–C distances, Mulliken, atomic natural population (NPA) and Merz-Kollman (MK) charges, bond orders, stabilization and solvation energies, frontier orbitals, some descriptors and their topological properties were compared with the antihistaminic cyclizine agent. The frontier orbitals studies show that the free base species of both forms in solution are more reactive than cyclizine. Higher electrophilicity indexes are observed in the cationic and hydrochloride species of PTZ than cyclizine while the cationic species of cyclizine have higher nucleophilicity index than both species of PTZ. The presences of bands attributed to cationic species of both enantiomers are clearly supported by the infrared and Raman spectra in the solid phase. The expected 114, 117 and 120 vibration normal modes for the free base, cationic and hydrochloride species of both forms were completely assigned and the force constants reported. Reasonable concordances among the predicted infrared, Raman, UV-Vis and Electronic Circular Dichroism (ECD) with the corresponding experimental ones were found.

Structural and vibrational studies of equilenin, equilin and estrone steroids

“…Apparently, the higher global electrophilicity value evidenced by equilenin is related to its higher reactivity and with the less negative nucleophilicity value. The comparisons of these gap values of three steroids species with other such as the free base, cationic and hydrochloride species of alkaloids or antihistaminic agents [48][49][50][51][52][53][54][55][56][57] are interesting to know how the different groups and rings present in their structures have influence on their reactivities and behaviours in the different media. Thus, the gap value of 4.5008 eV for equilenin is similar to those observed for the hydrochloride species of morphine (4.5840 eV) and of the R(+) form of promethazine (4.4926 eV) while the values of 5.4695 and 5.4342 eV observed for equilin and estrone, respectively are similar to value predicted for the cationic species of cocaine (5.4468 eV).…”

DFT study of species derived from the narcotic antagonist naloxone

“…In Table 2 are presented solvation energy values corrected and uncorrected by the total non-electrostatic terms and by zero point vibrational energy (ZPVE) for the three species of naloxone in aqueous solution by using the functional hybrid B3LYP/6-31G* method. The corrected solvation energy values are compared with those reported for some alkaloids [1][2][3]5,7] and for antihistaminic species [8,17]. The behaviours of all species in both media are given in Figure 2.…”

“…DFT calculations are very useful tools to analyse structures and predict properties of numerous compounds with different fused rings [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], such as tropane alkaloids. These alkaloids contain the >N-CH 3 group and present a wide range of biological properties and different structural, electronic and topological properties some of which were studied by our research group [1][2][3][4][5][6][7].…”

“…In the free base, cationic and hydrochloride species of these alkaloids can be observed a N atom tertiary where the N-C distance plays a very important role in the stability of species and where changes in the charges, in the electronic densities of rings, stabilization and solvation energies were detected when the >N-CH 3 group is linked to fused or alone rings [7]. Besides, the >N-CH 3 group can be present in other species that present antihistaminic properties, as in promethazine, diphenidramine and cyclizine [8,16,17]. On the other hand, the studies in solution have revealed that in the solid phase and in aqueous solution the hydrochloride/hydrobromide form is clearly present as cationic one, as suggested by its infrared and Raman spectra [1][2][3][5][6][7][8]16,17].…”

“…Besides, the >N-CH 3 group can be present in other species that present antihistaminic properties, as in promethazine, diphenidramine and cyclizine [8,16,17]. On the other hand, the studies in solution have revealed that in the solid phase and in aqueous solution the hydrochloride/hydrobromide form is clearly present as cationic one, as suggested by its infrared and Raman spectra [1][2][3][5][6][7][8]16,17]. In this work, the structures and properties of naloxone narcotic agent were studied combining DFT calculations with experimental data because in this species the N atom tertiary is linked to allyl >N-CH 2 -CH=CH 2 group different from the N-CH 3 group.…”