Electrostatic properties of two precursors of potent HIV-1 integrase inhibitors

International audiencecompounds can give a better insight into the properties of hydrogen bonds and of other, weaker, non-covalent interactions in these systems. This can, in turn, be helpful for getting a better understanding of the conformational changes induced by temperature, pressure, or chemicals in the biopolymers built from amino acids (peptides). In the contribution we shall illustrate this by the results of recent X-ray single-crystal and X-ray powder diffraction, Raman and IR-spectroscopy studies at variable temperatures and pressures, as well as of the DSC and adiabatic calorimetry studies from 5K to the decomposition temperatures. [1] Boldyreva E.V., et. al. The structure of the inclusion complex of-cyclodextrin (-CD) with ibuprofen has been determined as part of a study of-CD complexes with non steroidal anti-inflammatory drug molecules and similar organic compounds. Ibuprofen is a hydrophobic molecule but becomes soluble in water by complexation with-CD. This complex forms dimers in the crystalline state. Very often-CD complexes crystallize as dimers linked head to head by hydrogen bonds between secondary hydroxyls. These dimers form infinite two dimensional layers in a C2 unit cell. The extended crystal structure is built up by linking together the layers in different packing modes. As well as the substantial pharmaceutical interest of describing the interaction between the drug and the CD molecule in the crystalline complex, one of our goals was to investigate how the nature of the guest and the solvent molecules influences the packing mode in the crystal, how the hydrogen bonding interactions are important in the supramolecular structure, and how order-disorder phenomena observed in analogous compounds can be explained. In these studies, we have used X-ray and neutron diffraction data, as well as X-ray diffuse scattering patterns. The results of the X-ray diffuse scattering analyses will not be described here. Here we report the first neutron diffraction structure of a dimeric-CD complex (at 15K) and the comparison with the Synchrotron X-ray structure (at 300K). New AIDS therapy developments focus on the integrase inhibition in order to block the virus replication. Quinoline derivatives are potent drugs in this novel chemotherapy [1]. These molecules are formed by a quinoline moiety connected to a hydroxylated aromatic ring through a spacer fragment. This latter plays an important role in both inhibition and toxicity of the drugs. We have carried out the study of electrostatic properties of the two main precursors. These properties are derived experimentally from high-resolution X-ray diffraction experiments and from quantum mechanics calculations at Hartree-Fock level. The topological features of the electron density of precursors are carefully analyzed. The atomic charges and the electrostatic potential are discussed to highlight the correlation between the drug activity and the electronic structure. We compare molecular geometry and interactions of new potential sweeteners which were designed using chemical modification of a known sweet compound [1] and bioisosteric replacement. We determined crystal structures of three arylsulfonylalcanoic acids and one bioisoster containing a tetrazole instead of the carboxylic group. Unfortunately, last of them occured to be bitter. However, it is not very surprising since the sweet and bitter tastes are strongly related. According to the geometrical model of glucophore given by Kier, there are three fundamental fragments of a sweet compound which interact with a sweet taste receptor [2]. A sweetener should contain a donor and an acceptor of hydrogen bond and a fragment which can be involved in hydrophobic interactions [3]. Distances between those fragments define a glucophore. However, the geometry of our sweet compounds in the crystalline state do not agree with the Kier model. We observed a pair of very strong hydrogen bonds in sweet compounds building a dimer via inversion centre whereas in tetrazole the dimeric structure does not occur. That can explain why the bioisoster is bitter