ABSTRACT
2-Iminocoumarin-3-carboxamide (2-imino-2â H-chromene-3-carboxylic acid) is a perspective compound for use in the pharmaceutical industry. This compound crystallized from several solvents as two concomitant polymorphic forms. The monoclinic polymorph, crystallized initially, is formed due to strong N-H...O hydrogen bonds, weak C-H...O and C-H...N(π) hydrogen bonds, and stacking interactions of `head-to-head' type. The triclinic polymorphic form obtained due to slow evaporation of the same solution is formed due to only strong intermolecular interactions, N-H...O hydrogen bonds of two types, and stacking interactions of two types. Analysis of pairwise interaction energies showed that the monoclinic structure is columnar while the triclinic one is layered. Calculations in a periodic approximation of their lattice energies confirmed that the monoclinic polymorphic crystals are metastable as compared to the stable triclinic polymorph. Further quantum chemical modeling of possible structure deformations proved that both concomitant polymorphs can not be transformed into a new polymorphic form under external influence.
ABSTRACT
Polymorphism of 6-methyluracil, which affects the regulation of lipid peroxidation and wound healing, has been studied by experimental and quantum chemical methods. Two known polymorphic modifications and two new crystalline forms were crystallized and characterized by single crystal and powder X-ray diffraction (XRD) methods as well as by the differential scanning calorimetry (DSC) method and infrared (IR) spectroscopy. The calculations of pairwise interaction energies between molecules and lattice energies in periodic boundary conditions have shown that the polymorphic form 6MU_I used in the pharmaceutical industry and two new forms 6MU_III and 6MU_IV, which can be formed due to temperature violations, may be considered as metastable. The centrosymmetric dimer bound by two N-H···O hydrogen bonds was recognized as a dimeric building unit in all of the polymorphic forms of 6-methyluracil. Four polymorphic forms have a layered structure from the viewpoint of interaction energies between dimeric building units. The layers parallel to the (100) crystallographic plane were recognized as a basic structural motif in the 6MU_I, 6MU_III, and 6MU_IV crystals. In the 6MU_II structure, a basic structural motif is a layer parallel to the (001) crystallographic plane. The ratio between the interaction energies within the basic structural motif and between neighboring layers correlates with the relative stability of the studied polymorphic forms. The most stable polymorphic form 6MU_II has the most anisotropic "energetic" structure, while the interaction energies in the least stable form 6MU_IV are very close in various directions. The modeling of shear deformations of layers in the metastable polymorphic structures has not revealed any possibility of these crystals to be deformed under external mechanical stress or pressure influence. These results allow the use of metastable polymorphic forms of 6-methyluracil in the pharmaceutical industry without any limitations.
ABSTRACT
Three polymorphic structures of mefenamic acid, which is a very popular drug, have been studied using quantum chemical methods. It has been shown that the centrosymmetric dimer formed due to two O-H···O hydrogen bonds is a complex building unit in all of the polymorphic structures under study. On the basis of an analysis of the pairwise interaction energies between molecules, the polymorphic forms I and II are classified as columnar-layered while the polymorphic form III has a columnar structure. The stabilities of the three polymorphic forms of mefenamic acid under ambient conditions (I > II > III) correlate with the degree of anisotropy of the interaction energies between columns (primary basic structural motifs) formed due to stacking interactions. The shear deformation modeling of strongly bound layers in all of the polymorphic structures has not revealed any possibility for deformation of the crystal structure. The construction of the shift energy profiles and calculation of the energy barriers for the displacement along the (100) crystallographic plane in the [100], [010], and [011] crystallographic directions make it possible to explain the experimental data obtained for commercially available polymorphic structure I in a diamond anvil cell. The absence of any local minimum near the starting point on the shift energy profile and the extremely high energy barrier can be considered as criteria for the impossibility of a crystal structure deformation under pressure.
ABSTRACT
Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner-Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combination of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity.
