175968-16-8Relevant academic research and scientific papers
SMALL MOLECULE INHIBITORS OF THE BFRB:BFD INTERACTION
-
Paragraph 0106; 0113; 0199, (2020/07/05)
The present technology provides compounds of Formula I and related methods for treating a bacterial infection as well as methods for inhibiting interaction of a bacterioferritin and a bacterioferritin-associated ferredoxin.
Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity
Hewage, Achala N. D. Punchi,Yao, Huili,Nammalwar, Baskar,Gnanasekaran, Krishna Kumar,Lovell, Scott,Bunce, Richard A.,Eshelman, Kate,Phaniraj, Sahishna M.,Lee, Molly M.,Peterson, Blake R.,Battaile, Kevin P.,Reitz, Allen B.,Rivera, Mario
supporting information, p. 8171 - 8184 (2019/06/13)
The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- A nd 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell.
COMPOUNDS, SALTS THEREOF AND METHODS FOR TREATMENT OF DISEASES
-
Paragraph 00327-00328, (2019/03/12)
The present disclosure relates to compounds according to Formula (I), useful for treating diseases.
ANTIDIABETIC BICYCLIC COMPOUNDS
-
Page/Page column 176, (2016/04/04)
Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
PHENYLAZETIDINONE DERIVATIVES
-
Page/Page column 290-291, (2008/06/13)
Various azetidinone derivatives are described, as are pharmaceutical compositions containing these compounds and methods of treatment of diseases using these compounds. Other embodiments are also described.
Unexpected Regioselectivity in the Lithiation of Fluoroanisoles
Furlano, David C.,Calderon, Silvia N.,Chen, George,Kirk, Kenneth L.
, p. 3145 - 3147 (2007/10/02)
The regioselectivity of lithiation of a series of fluoroanisoles and fluoroveratroles has been studied by determining the ratio of isomeric aldehydes produced by dimethylformamide quenching.The position of lithiation is influenced by such factors as temperature and time of the reaction.Contrary to published reports, fluorine competes significantly with the methoxy group as an ortho director in lithiation reactions.Lithiation of dimethyl-tert-butylsilyl ethers of fluorophenols proceeds exclusively ortho to fluorine.
