The application of parallel synthesis to lead optimization programs in drug discovery has been an ongoing challenge since the first reports of library synthesis. A number of approaches to the application of parallel array synthesis to lead optimization have been attempted over the years, ranging from widespread deployment by (and support of) individual medicinal chemists to centralization as a service by an expert core team. This manuscript describes our experience with the latter approach, which was undertaken as part of a larger initiative to optimize drug discovery. In particular, we highlight how concepts taken from the manufacturing sector can be applied to drug discovery and parallel synthesis to improve the timeliness and thus the impact of arrays on drug discovery.
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http://dx.doi.org/10.1021/cc050164h | DOI Listing |
ChemMedChem
December 2024
University of Ljubljana, Faculty of Pharmacy, Askerceva cesta 7, 1000, Ljubljana, SLOVENIA.
Seven different enzymes comprise the galactosyltransferases family, of which β-1,4-galactosyltransferase I (β-1,4-GALT1) is the major contributor to galactosylation activity in cells. Since abnormalities in galactosylation are associated with many pathophysiological conditions, β-1,4-GALT1 is an interesting new target for drug discovery and molecular probe design. There are several known β-1,4-GALT1 inhibitors, but most of them suffer from low cell permeability and thus low in vivo activity.
View Article and Find Full Text PDFChemistry
December 2024
University of Liverpool, Department of Chemistry, Oxford Street, L69 7ZD, Liverpool, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
The Zincke reaction and Birch reduction have been one of the few reactions that allow for ring opening of pyridines ever since the discovery of pyridine more than a century ago. This paper presents a new addition to the list of pyridine ring-opening reactions, reductive Zincke reaction, which affords saturated δ-amino ketones. Under the catalysis of a simple rhodium complex, pyridinium salts with diverse substituents are reduced with formic acid, ring-opened with water, transaminated with a secondary amine and further reduced to afford a wide range of δ-amino ketones, including those in which the alkane chain of the ketones is selectively deuterated or fluorinated.
View Article and Find Full Text PDFChemistry
December 2024
Osaka University, Graduate School of Pharmaceutical Sciences, 1-6, Yamada-oka, 565-0871, Osaka, JAPAN.
Deuterated molecules are of growing interest because of the specific characteristics of deuterium, such as stronger C-D bonds being stronger than C-H bonds. Polyethylene glycols (PEGs) are widely utilized in scientific fields (e.g.
View Article and Find Full Text PDFChempluschem
December 2024
Indian Institute of Technology Jodhpur, Chemistry, Jodhpur, 342037, Jodhpur, INDIA.
Herein, we present a distorted square pyramidal mercury complex, [HgII(L)Cl] (1), based on a quinoline-substituted formazan ligand LH[3-Cyano-1,5-(quinolin-8-yl)formazan], which was evaluated for its anti-bacterial activity in vitro. Complex 1 was prepared by refluxing 3-Cyano-1,5-(quinolin-8-yl)formazan ligand and mercury chloride(II) in equimolar quantity and was characterized utilizing a range of analytical methods, including single crystal X-ray diffraction (SCXRD) technique. The crystal packing in complex 1 has been elucidated using supramolecular investigations, which have shown the presence of fascinating Hg-Cl···Hg intermolecular spodium bonds of the order 3.
View Article and Find Full Text PDFJ Med Chem
December 2024
Department of Chemistry, School of Science and Engineering, Saint Louis University, Saint Louis, Missouri 63103, United States.
Cryptosporidiosis is a diarrheal disease caused by the parasite resulting in over 100,000 deaths annually. Here, we present a structure-activity relationship study of the benzoic acid position (R) of pyrazolo[3,4-]pyrimidine lead SLU-2815 (), an inhibitor of parasite phosphodiesterase PDE1, resulting in the discovery of benzoxaborole SLU-10906 () as a benzoic acid bioisostere. Benzoxaborole is 10-fold more potent than against the parasite in a cell-based infection model (EC = 0.
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