Progress in the Understanding of Drug–Receptor Interactions, Part 1: Experimental Charge‐Density Study of an Angiotensin II Receptor Antagonist (C₃₀H₃₀N₆O₃S) atT=17 K

Abstract

An experimental study of the electron-density distribution rho(r) in an angiotensin II receptor antagonist 1 has been made on the basis of single-crystal X-ray diffraction data collected at a low temperature. The crystal structure of 1 consists of infinite ribbons in which molecules are connected by an N-H...N hydrogen bond and several interactions of the C-H...O, C-H...N, and C-H...S type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a phenyl spacer group, is stabilized by two short SO and SN intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these interactions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the sulfur, oxygen, and nitrogen atoms involved in these interactions shows their strongly directional character as the regions of charge concentration on the valence shell of the nitrogen and oxygen atoms directly face the regions of charge depletion on the valence shell of the sulfur atom. All the chemical bonds and the relevant intra- and intermolecular interactions of 1 have been quantitatively described by the topological analysis of rho(r). Simple relationships between the bond path lengths (R(b)) and the values of rho at the bond critical points (rho(bcp)) have been obtained for the 28 C-C bonds, the seven N-C bonds, and the four O-C bonds. For the first two classes of bonds the relationship is in the form of a straight line, whose parameters, for the C-C bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction study of crystals of a different compound. Maps of the molecular electrostatic potential phi(r) derived from the experimental charge density display features that are important for the drug-receptor recognition of 1.

Progress in the Understanding of Drug–Receptor Interactions, Part 2: Experimental and Theoretical Electrostatic Moments and Interaction Energies of an Angiotensin II Receptor Antagonist (C30H30N6O3S)

“…[36,37] The same role has been suggested in Paper 1 for the observed 1,6-type S···O close contact in 1 on the basis of the experimental geometry. [15] This hypothesis is now reinforced by the theoretical results, which indicate the same favourable interaction is also present in the gas-phase geometry. Interestingly, this fits very well with a feature observed in both AII and peptide AII antagonists such as Sarmesin in numerous quantitative structure-activity relationship (QSAR), conformational and modelling studies, [1c, 4, 38, 39] which showed the existence of short, stabilising intramolecular contacts between the side-chain aromatic rings of the triad key amino acids Tyr .…”

“…[15] They can be summarised briefly as follows: a total of 51 485 intensities were collected at T = 17(1) K up to a 2q value of 758 for graphite-monochromated Mo Ka radiation. [20] Weighted averaging of multiple data yielded 14 698 independent reflections of which 13 812 were observed (I > 0).…”

“…[15] In that paper, hereinafter referred to as Paper 1, the structural features of 1 were thoroughly discussed and both the full topological analysis of its experimental charge density distribution 1(r) and the molecular electrostatic potential f(r) were presented. This allowed us to clarify important features of intra-and intermolecular interactions, such as the electrostatic nature of two short S···O and S···N intramolecular contacts that stabilise the overall conformation of 1, and to elucidate the f(r) features which play a key role in the binding to the AII receptor.…”

“…The thiophene, the pyrimidinone and the tetrazole rings are linked in a cyclic structure by three short intramolecular contacts, namely N4···H9 (2.751(6) ), S1···N5 (3.2950(3) ) and S1···O1 (3.1995(3) ), with the associated topological rings (see Paper 1). [15] This structure is further stabilised by the H5A···O3 interaction (2.200(6) ) which locks the 3-substituted thiophene in a favourable conformation.…”

“…In agreement with one of the rules for the packing of hydrogenbonded crystals proposed by Bertolasi et al, [35] this bond does not occur in the crystal; instead the N6 À HN6 group is involved in a competing intermolecular hydrogen bond with the N1 atom of the pyrimidinone ring of another molecule. [15] The role of intramolecular non-covalent S···O interactions in the conformation and activity of biologically important systems has been investigated in the case of 1,4-and 1,5-type interactions. [36,37] The same role has been suggested in Paper 1 for the observed 1,6-type S···O close contact in 1 on the basis of the experimental geometry.…”