Abstract:
(See Tue - P46 in URL above). Tuberculosis (TB) is still a major global public health threat – a persistent epidemic that currently afflicts over 11 million people worldwide. Although TB can be treated, the lengthy and complex treatment regimens are inadequate to contain the disease, especially its multidrug resistant (MDR) forms. Very few new drugs have been developed in the past 50 years, and there is a need for anti-TB agents with different modes of action. The nitroimidazooxazine Pretomanid (PA-824, 1) is representative of a new class of bioreductive TB drugs and is currently undergoing Phase II/III clinical trials as part of a novel combination of agents (with bedaquiline, moxifloxacin and pyrazinamide) which can potentially reduce treatment duration and complexity. During the course of our studies, we became interested in the biological activity of the 3-nitro isomer of Pretomanid (2). The synthesis of 2 proved to be very challenging. The key and limiting step of the synthesis was a nitration reaction, involving the dihydro-imidazooxazinol intermediate 3. We report here our optimization of the synthetic route, allowing us to prepare 10 g of the desired final target 2. The structure of 2 was confirmed by X-ray crystallography. Preliminary data on its biological activity are also reported.
