ABSTRACT
We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.
Subject(s)
HIV Integrase/chemistry , Integrase Inhibitors/chemistry , Models, Chemical , Quinolines/chemistry , Carbon Isotopes , Crystallization , Enzyme Activation/drug effects , HIV Integrase/drug effects , Integrase Inhibitors/pharmacology , Magnetic Resonance Spectroscopy/methods , Models, Molecular , Molecular Structure , Oxidation-Reduction , Predictive Value of Tests , Quantum Theory , Quinolines/chemical synthesis , Quinolines/pharmacology , Sensitivity and Specificity , Static Electricity , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
Both 7-carboxylato-8-hydroxy-2-methylquinolinium monohydrate, C11H9NO3.H2O, (I), and 7-carboxy-8-hydroxy-2-methylquinolinium chloride monohydrate, C11H10NO3+.Cl-.H2O, (II), crystallize in the centrosymmetric P-1 space group. Both compounds display an intramolecular O-H...O hydrogen bond involving the hydroxy group; this hydrogen bond is stronger in (I) due to its zwitterionic character [O...O = 2.4449 (11) A in (I) and 2.5881 (12) A in (II)]. In both crystal structures, the HN+ group participates in the stabilization of the structure via intermolecular hydrogen bonds with water molecules [N...O = 2.7450 (12) A in (I) and 2.8025 (14) A in (II)]. In compound (II), a hydrogen-bond network connects the Cl- anion to the carboxylic acid group [Cl...O = 2.9641 (11) A] and to two water molecules [Cl...O = 3.1485 (10) and 3.2744 (10) A].
