title: Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824.
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.
authors: Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors: Xiaojin
authors: X
authors: Li
authors: Ujjini H
authors: UH
authors: Manjunatha
authors: Michael B
authors: MB
authors: Goodwin
authors: John E
authors: JE
authors: Knox
authors: Christopher A
authors: CA
authors: Lipinski
authors: Thomas H
authors: TH
authors: Keller
authors: Clifton E
authors: CE
authors: Barry
authors: Cynthia S
authors: CS
authors: Dowd
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010078:Oxazines; D010080:Oxazoles; C410767:pretomanid