Christopher Lipinski - Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imida zo[2,1-b][1,3]oxazines, analogues of PA-824.

Document created by Christopher Lipinski on Aug 22, 2014
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  Publication Details (including relevant citation   information): Li, Xiaojin, Manjunatha, Ujjini H.,   Goodwin, Michael B., Knox, John E., Lipinski, Christopher A.,   Keller, Thomas H., Barry, Clifton E., Dowd, Cynthia S.,   Bioorganic & medicinal chemistry letters,   2008, 18 (7), pp 2256-2262

  Abstract: Nitroimidazoles such as PA-824 and   OPC-67683 are currently in clinical development as members of a   promising new class of therapeutics for tuberculosis. While the   antitubercular activity of these compounds is high, they both   suffer from poor water solubility thus complicating development.   We determined the single crystal X-ray structure of PA-824 and   found a close packing of the nitroimidazoles facilitated by a   pseudoaxial conformation of the p-trifluoromethoxybenzyl ether.   To attempt to disrupt this tight packing by destabilizing the   axial preference of this side chain, we prepared the two   diastereomers of the 7-methyl-nitroimidazo-oxazine. Determination   of the crystal structure of the 7-(S)-methyl derivative (5, cis)   revealed that the benzylic side chain remained pseudoaxial while   the 7-(R)-methyl derivative (6, trans) adopted the desired   pseudoequatorial conformation. Both derivatives displayed similar   activities against Mycobacterium tuberculosis, but neither showed   improved aqueous solubility, suggesting that inherent lattice   stability is not likely to be a major factor in limiting   solubility. Conformational analysis revealed that all three   compounds have similar energetically accessible conformations in   solution. Additionally, these results suggest that the   nitroreductase that initially recognizes PA-824 is somewhat   insensitive to substitutions at the 7-position.

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