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Kalamazoo, MI, United States

Walker D.,Kalexsyn Inc. | Rogier D.J.,Kalexsyn Inc.
Synthesis (Germany) | Year: 2013

Thiomorpholine and thiomorpholine 1,1-dioxide are important building blocks in medicinal chemistry research, and some analogues containing these moieties have entered human clinical trials. Analogues containing bridged bicyclic thiomorpholines have also shown interesting biological profiles. 3-Thia-6-azabicyclo[3.1.1]heptane, 3-thia-8-azabicyclo[3.2.1]octane, and their corresponding 1,1-dioxide counterparts were prepared as novel bicyclic thiomorpholine building blocks. Each heterocycle was synthesized from an inexpensive starting material by straightforward chemistry. © Georg Thieme Verlag Stuttgart, New York. Source


Wuts P.G.M.,Kalexsyn Inc. | Simons L.J.,Kalexsyn Inc. | Metzger B.P.,Aureogen Biosciences, Inc. | Sterling R.C.,Aureogen Biosciences, Inc. | And 2 more authors.
ACS Medicinal Chemistry Letters | Year: 2015

The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 μg/mL. The approach is readily adaptable to large-scale synthesis and industrial production. © 2015 American Chemical Society. Source


Miller J.R.,Pfizer | Miller J.R.,Merck And Co. | Thanabal V.,Pfizer | Melnick M.M.,Pfizer | And 9 more authors.
Chemical Biology and Drug Design | Year: 2010

High-throughput screening is utilized by pharmaceutical researchers and, increasingly, academic investigators to identify agents that act upon enzymes, receptors, and cellular processes. Screening hits include molecules that specifically bind the target and a greater number of non-specific compounds. It is necessary to 'triage' these hits to identify the subset worthy of further exploration. As part of our antibacterial drug discovery effort, we applied a suite of biochemical and biophysical tools to accelerate the triage process. We describe application of these tools to a series of 9-oxo-4,9-dihydropyrazolo[5, 1-b]quinazoline-2-carboxylic acids (PQ) hits from a screen of Escherichia coli phosphopantetheine adenylyltransferase (PPAT). Initial confirmation of specific binding to phosphopantetheine adenylyltransferase was obtained using biochemical and biophysical tools, including a novel orthogonal assay, isothermal titration calorimetry, and saturation transfer difference NMR. To identify the phosphopantetheine adenylyltransferase sub-site bound by these inhibitors, two techniques were utilized: steady-state enzyme kinetics and a novel 19F NMR method in which fluorine-containing fragments that bind the ATP and/or phosphopantetheine sites serve as competitive reporter probes. These data are consistent with PQs binding the ATP sub-site. In addition to identification of a series of PPAT inhibitors, the described hit triage process is broadly applicable to other enzyme targets in which milligram quantities of purified target protein are available. © 2010 John Wiley & Sons A/S. Source


Schlauderer F.,Ludwig Maximilians University of Munich | Lammens K.,Ludwig Maximilians University of Munich | Nagel D.,Helmholtz Center Munich | Vincendeau M.,Helmholtz Center Munich | And 7 more authors.
Angewandte Chemie - International Edition | Year: 2013

Second site: In the crystal structure of human MALT1casp-Ig3 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) in complex with the tricyclic phenothiazine derivative thioridazine (violet in the picture), the inhibitor is bound in a hydrophobic pocket far from the active site. This explains the action of phenothiazine derivatives as noncompetitive, reversible inhibitors. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Bridged bicyclic piperazines are important building blocks in medicinal chemistry research. The bicyclic piperazine 3,6-diazabicylo[3.1.1]heptane is of particular interest as a piperazine isostere because it is achiral and shows similar lipophilicity to that of piperazine based on the c Log P of a derived analog. A concise synthesis of N 3- and N 6-monoprotected 3,6-diazabicyclo[3.1.1]heptanes 2d and 2e, respectively, is described. The seven step sequence begins with inexpensive starting materials and uses straightforward chemistry. © 2012 Elsevier Ltd. All rights reserved. Source

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