Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

The total charge density of PYRAC, a polar (<i>Pca</i>2₁) organic racemate with <i>Z</i>′ = 2, was derived from high-resolution single-crystal X-ray diffraction data at <i>T</i> = 100(2) K and periodic DFT calculations. The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally different enantiomers, A and B_i, where the subscript “i” indicates a reversed absolute configuration. The lattice stability was compared with that of centrosymmetric possibly competing structures, with the aim of understanding why a noncentrosymmetric lattice framework is obtained from a racemic mixture. The likelihood of specific intermolecular recognition processes among different conformers of PYRAC in the very first stages of nucleation was investigated by DFT simulations in vacuo. Two competing, equivalent interconversion pseudorotatory paths between the most stable A and the least stable B conformers were found. It results that molecules spend most of their time (≈53%) in the A conformation, whereas the B one is far less populated (≈7%). Therefore, centrosymmetric AA_i adducts are formed very frequently in the reaction liquor, whereas the BB_i ones are rare. Nevertheless, AA_i pairs produce crystal forms with cohesive energies and densities significantly less favorable than those estimated for the noncentrosymmetric heterochiral AB_i ones. Therefore, preference for <i>Z</i>′ = 2 in conjunction with noncentrosymmetric point and space groups results from the thermodynamic control of the crystallization process. The capability of forming extended hydrogen bond chains throughout the lattice appears to be a prerequisite to bind together the fundamental AB_i repeating units

Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

The total charge density of PYRAC, a polar (<i>Pca</i>2₁) organic racemate with <i>Z</i>′ = 2, was derived from high-resolution single-crystal X-ray diffraction data at <i>T</i> = 100(2) K and periodic DFT calculations. The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally different enantiomers, A and B_i, where the subscript “i” indicates a reversed absolute configuration. The lattice stability was compared with that of centrosymmetric possibly competing structures, with the aim of understanding why a noncentrosymmetric lattice framework is obtained from a racemic mixture. The likelihood of specific intermolecular recognition processes among different conformers of PYRAC in the very first stages of nucleation was investigated by DFT simulations in vacuo. Two competing, equivalent interconversion pseudorotatory paths between the most stable A and the least stable B conformers were found. It results that molecules spend most of their time (≈53%) in the A conformation, whereas the B one is far less populated (≈7%). Therefore, centrosymmetric AA_i adducts are formed very frequently in the reaction liquor, whereas the BB_i ones are rare. Nevertheless, AA_i pairs produce crystal forms with cohesive energies and densities significantly less favorable than those estimated for the noncentrosymmetric heterochiral AB_i ones. Therefore, preference for <i>Z</i>′ = 2 in conjunction with noncentrosymmetric point and space groups results from the thermodynamic control of the crystallization process. The capability of forming extended hydrogen bond chains throughout the lattice appears to be a prerequisite to bind together the fundamental AB_i repeating units

Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria

We developed a new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry. Substituents on the isoxazolinic ring modulated the potency up to 20-fold, predominantly due to an electrostatic effect, as assessed by computational analysis

Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the <i>N</i>‑Methyl‑d‑aspartate Receptor as Potential Imaging Agents for Brain

Abnormal activity of various <i>N</i>-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer’s disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of <i>para</i>-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds <b>4a</b>–<b>c</b> and <b>4e</b> showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [^124/125I]<b>4d</b> and [¹¹C]<b>4e</b> (i.e., [^124/125I]<b>11d</b> and [¹¹C]<b>11e</b>) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [¹²⁵I]<b>11d</b> and [¹¹C]<b>11e</b> through autoradiography and biodistribution studies, imaging of neither [¹²⁴I]<b>11d</b> nor [¹¹C]<b>11e</b> could demonstrate brain penetration sufficient for detection by PET

Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors

Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer’s disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1–3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with <i>K</i>_i of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (<i>K</i>_i of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function