Mycobacterium tuberculosis growth inhibitors

Novel inhibitors of Mycobacterium tuberculosis growth based on modified pyrimidine nucleosides and their analogues 13UK896. 

G Harth, MA Horwitz (1999) An inhibitor of exported Mycobacterium tuberculosis glutamine synthetase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes extracellular proteins as potential novel drug targets, J Exp Med 189(9) 1425-1436... 

Whole cell growth inhibition screens combined with subsequent target identification using molecular methods have proven viable approaches to the discovery of novel antibacterial inhibitors. Andries and colleagues (2005) at Johnson Johnson employed whole cell assays to discover a series of antimycobacterial diarylquinolines (DARQs). Chemical optimization of a lead compound led to DARQ derivatives exhibiting potent in vitro activities against several mycobacteria including Mycobacterium tuberculosis (Andries et al., 2005 Ji et al., 2006), with MICs below 0.5 pg/mL. Antimycobacterial efficacy in vivo was confirmed for three of the derivatives. 

Ethyldiazoacetate (EDAC) has become a commonly utilized 1,3-dipole in the Pechmann pyrazole synthesis. In efforts toward the rational design of growth inhibitors of Mycobacterium tuberculosis, Kozikowski and co-workers utilized this strategy for the synthesis of the pyrazole ester. Treatment of a mixture of alkyne and EDAC under microwave conditions resulted in the preparation of the pyrazole ester as a mixture of H and 2H tautomers. The pyrazole ester proved inactive in the anti-TB assay, thereby proving the importance of an isoxazole moiety for anti-TB activity, as previous work by these authors suggested. ... 

Wei, X., Rodriguez, A.D., Wang, Y, and Franzblau, S.G. (2007) Novel ring abeo-sterol as growth inhibitors of Mycobacterium tuberculosis isolated from a Caribbean sea sponge, Svenzea zeai. Tetrahedron Lett., 48, 8851-8854. 

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