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. KeywordsMycobacterium tuberculosis; PA-824; solubility Despite decades of research, tuberculosis continues to be a major public health threat. The WHO estimates that, in 2005, 1.6 million people died from tuberculosis (TB) which is caused *Corresponding author: Department of Chemistry, George Washington University, 725 21st St. NW, Corcoran Hall 107, Washington DC 20052, Tel: 202-994-8405 Fax: 202-994- Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. by the microorganism Mycobacterium tuberculosis (Mtb). 1 Current therapy for TB lasts for several months and is called directly-observed therapy short-course (DOTS). This regimen calls for an intensive phase of chemotherapy using four drugs for 2 months, followed by a continuation phase using two drugs for 4-6 months. 2 Rifampin is inarguably the most important drug in the DOTS regimen as it allowed shortening the course of therapy to 6 months from the standard 12-18 months of previous regimens. The potency of rifampin is thought to be due in part to its action against both aerobically-growing and anaerobically-adapted, nonreplicating mycobacteria. 3 NIH Public AccessNitroimidazoles are a class of compounds widely used clinically for the management of a...

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