Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof
Abstract
The present invention provides aryl- or heteroaryl-diketo acid compounds effective to inhibit an activity of a Mycobacterial malate synthase enzyme or to inhibit a malate synthase activity in other bacteria having the enzyme. The compounds may be phenyl- naphthyl-, or thienyl-substituted diketo acids and carboxylate derivatives thereof. Also provided are methods of treating tuberculosis or other pathophysiological conditions associated with a malate synthase enzyme with the inhibitory compounds and methods of in silico design of the inhibitory compounds. In addition, the present invention provides the inhibitory compounds designed by this method. Furthermore, three-dimensional X-ray crystal structures of the Mycobacterial malate synthase complexed with the inhibitory compounds are provided. Further still a method for stabilizing an aromatic or heteroaromatic diketo acid or its prodrug or close analog in solution by derivatizing at least the ortho position on the aromatic ring is provided.
Subject
514/399514/425
514/545
514/570
548/333.5
548/530
568/303
C07D 233/54
A61K 31/235
C07D 333/24
C07D 333/54
C07D 307/80
C07C 59/88
C07D 307/54
A61K 31/505
C12Q 1/527
A61K 45/06
C07C 59/84
C07D 213/55
C07D 333/22
C07D 333/56
C07D 207/44
A61K 31/19
C07D 213/50
C07D 333/60
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C07D 333/06
C07D 233/64
A61K 31/4164
A61K 31/343
A61K 31/4015
A61P 31/06
C07D 239/20
A61K 31/341
A61K 31/381
A61K 31/4402
C07D 307/46
C07C 59/90
C07C 69/738
A61P 31/04
C07D 207/404
C07C 317/46
Collections
Citation
Freundlich, Joel S.; Sacchettini, James C.; Kriger, Inna V.; Ioerger, Thomas R.; Gawandi, Vijay (2014). Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof. United States. Patent and Trademark Office; Texas A&M University. Libraries. Available electronically from https : / /hdl .handle .net /1969 .1 /177061.