Main Group Metal Halide Complexes with Sterically Hindered Thioureas XI. Complexes of Antimony(III) and Bismuth(III) Chlorides with a New Bidentate Thiourea — 1,1′-methylenebis(3-methyl-2H-imidazole-2-thione)

Bidentate 1,1\u27-methylenebis(3-methyl-2H-imidazole-2-thione) (L), SbCl3L, and BiCl3L were synthesized and characterized. SbCl3L is monoclinic, space group P21/c, a 11.812(9), b 7.699(4), c 18.100(9) Å, β 101.29(5)°, Z = 4, R = 0.042, Rw = 0.041. Geometry at Sb was distorted octahedral with bridging S atoms creating long zigzag chains of octahedra sharing vertexes cis to each other. Two Cl atoms are trans to each other, and the 3rd Cl is trans to the bridging S. The Sb-S bridges are 3.41 Å in length. There is not strong evidence for a stereospecific lone pair in the coordination sphere of Sb. The ligand forms an 8-membered ring with the Sb atom included. Solid state IR data showed little change in L vibrational modes normally sensitive to coordination; NMR gave evidence for a high degree of assocn

The Structure–Activity Relationship of a Tetrahydroisoquinoline Class of <i>N</i>‑Methyl‑d‑Aspartate Receptor Modulators that Potentiates GluN2B-Containing <i>N</i>‑Methyl‑d‑Aspartate Receptors

We have identified a series of positive allosteric NMDA receptor (NMDAR) modulators derived from a known class of GluN2C/D-selective tetrahydroisoquinoline analogues that includes CIQ. The prototypical compound of this series contains a single isopropoxy moiety in place of the two methoxy substituents present in CIQ. Modifications of this isopropoxy-containing scaffold led to the identification of analogues with enhanced activity at the GluN2B subunit. We identified molecules that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C, and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations of agonist. Multiple compounds potentiate the response of NMDARs with submicromolar EC₅₀ values. Analysis of enantiomeric pairs revealed that the <i>S</i>-(−) enantiomer is active at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the <i>R</i>-(+) enantiomer is only active at GluN2C/D subunits. These results provide a starting point for the development of selective positive allosteric modulators for GluN2B-containing receptors

Sphingolipid Analogues Inhibit Development of Malaria Parasites

<i>Plasmodium</i>-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species <i>Plasmodium falciparum</i> and <i>Plasmodium knowlesi</i>, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo

Discovery of a Fluorinated Enigmol Analog with Enhanced <i>in Vivo</i> Pharmacokinetic and Anti-Tumor Properties

The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous <i>in vivo</i> settings. However, as no Enigmol analog with enhanced potency <i>in vitro</i> has been identified, a new strategy to improve efficacy <i>in vivo</i> by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF₃-Enigmol and CF₂-Enigmol, are reported. Each analog was equipotent to Enigmol <i>in vitro</i>, but achieved higher plasma and tissue levels than Enigmol <i>in vivo</i>. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF₂-Enigmol absorbed into tissue at strikingly higher concentrations than CF₃-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF₃-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF₂-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol