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New Castle, DE, United States

Leonik F.M.,Adesis Inc. | Ghiviriga I.,University of Florida | Horenstein N.A.,University of Florida
Tetrahedron | Year: 2010

All-cis 1-hydroxymethyl 2, 3 bis-aminomethyl cyclopropane was used to construct the first 3, 5- diazabicyclo [5.1.0]-3-octenes. This system has the interesting ability to exist in a conformation that resembles a snapshot of a glycoside hydrolysis reaction with respect to charge and geometric analogy to an oxocarbenium ion, and the positioning of the departing aglycon. The cis-configured cyclopropane core was synthesized by Cu-catalyzed intramolecular cyclopropanation of benzyl protected cis-2-butene-1, 4- diol diazoacetate ester. Serial functionalization to bis-aminomethyl cyclopropanes and subsequent cyclization to amidines lead to the target bicyclic compounds in good overall yields. Several glycosidases were surveyed for the inhibitory potential of these transition state analogs, and amongst them, selective competitive inhibitors with micromolar Ki values were identified. © 2010 Elsevier Ltd. All rights reserved.


Reck F.,Astrazeneca | Ehmann D.E.,Astrazeneca | Dougherty T.J.,Astrazeneca | Newman J.V.,Astrazeneca | And 20 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKaand log D) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa. © 2014 Elsevier Ltd. All rights reserved.

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